Novel biomarkers for antitumor therapies and PRDX6 as a therapeutic cancer target

Abstract

Use of PRDX6 is a predictive survival marker for several tumor types and drug targets, as well as using PRDX6 inhibitors to sensitize cancer cells to HDACi, PD1 and PD-L1 inhibitors.

Description

[0001] NOVEL BIOMARKERS FOR ANTITUMOR THERAPIES AND PRDX6 AS A THERAPEUTIC CANCER TARGET CROSS-REFERENCE TO RELATED APPLICATIONS This International PCT application claims the benefit of U.S. Provisional Application Serial No. 63 / 471,172 filed June 5, 2023, the specification, claims and drawings of which are incorporated herein by reference in their entirety. GOVERNMENT INTEREST This invention was made with government support under grant numbers R41HL162212, and R01GM144749 awarded by National Institutes of Health (NIH). The government has certain rights in the invention. SEQUENCE LISTING The instant application contains contents of the electronic sequence listing (90245.01031- Sequence-Listing.xml; Size: 12,243 bytes; and Date of Creation: June 5, 2024, is herein brief TECHNICAL FIELD The present invention is directed to novel biomarkers that govern histone deacetylase (HDAC) inhibitor sensitivity in tumor cells, specifically the present invention describes the novel use of Peroxiredoxin 6 (PRDX6) is a predictive survival biomarker for several tumor types and therapeutic drug targets. BACKGROUND Despite tremendous progress in understanding the molecular mechanisms of tumorigenesis, many cancers are still untreatable. One of the major challenges in anticancer therapeutics is that many patients exhibit inherent or acquired drug resistance. This calls for more studies to understand their mechanisms of drug sensitivity as well as to determine the appropriate patient characteristics that can be targeted for effective treatment. Histone deacetylase (HDAC) inhibitors have emerged as attractive antitumor agents. Specifically, since HDAC inhibitors can induce cancer cell death while sparing normal tissues. Moreover, studies have shown that acquired drug resistance is in part governed by epigenetic mechanism regulated by HDACs. As monotherapies, HDAC inhibitors currently proves to be effective only in cutaneous T-cell lymphoma (CTCL) and peripheral T-cell lymphoma (PTCL). Numerous studies are underway to develop therapies by combining HDACi with other anticancer drugs. Two key questions remain to be answered before HDAC inhibitors can become broader and more efficacious antitumor drugs. First, scientists need to know whether isoform-specific HDAC inhibitors are potentially more effective therapeutic agents than pan HDAC inhibitors. Second, it must be determined why, in spite of broader antitumor activities of HDAC inhibitors in preclinical models, only a portion of patients with a given diagnosis have a therapeutic response. This underscores the importance of identifying markers of potential response or resistance to HDAC inhibitors. Finding effective predictive markers could help identify patients who are more likely to benefit from therapy and design better combination therapies. The present inventors previously developed a selective class I HDAC inhibitor known as Paragazole (OKI-5) which is the drug precursor of OKI-179, which exhibits highly potent antitumor activity in a xenograft model with minimal toxicity. To identify predictive biomarker for the Paragazole class of drug response, the present inventors performed a CRISPR a screen and identified Peroxiredoxin 6 (PRDX6) as a key candidate that governs colon cancer sensitivity to Paragazole. Overexpression of PRDX6 causes paragazole resistance while depletion of PRDX6 sensitizes cancer cells to this drug. In another example, programmed death-1 (PD1) and / or a programmed death ligand-1 (PD- L1) have been shown to be therapeutic targets for various cancers, such as non-small cell lung cancer (NSCLC). However, there exist a lack of biomarkers to determine if a PD1 or PD-L1 inhibitors will be effective. Neither are there effective methods of compositions to sensitize cells to response more effectively to PD1 or PD-L1 inhibitors. As can be seen from the above, there exists a need for effective biomarkers and combination therapeutics to enhance the effectiveness of HDACi and PD1 or PD-L1 inhibitors for the treatment of cancer. SUMMARY OF THE INVENTION In one aspect the present invention provides a method of treating cancer in a subject in need thereof. In this preferred example, the method of the invention includes the step of administering a therapeutically effective amount of a histone deacetylase inhibitor (HDACI) to a subject in need thereof, wherein the levels of PRDX6 in the cancer cell of the subject are at a level, when compared to a reference level, indicative that the subject will respond to the administration of a therapeutically effective amount a HDACI, such as OKI-179, largazole or OKI-5 as described herein. In another aspect the present invention provides a method for determining if a cancer patient is predicted to respond to the administration of HDACI therapy. In this preferred example, the method of the invention includes detecting in a sample of cancer cells from the patient, a level of gene expression of PRDX6, wherein the expression levels of the PRDX6 are indicative of whether the patient will respond to the administration of a therapeutically effective amount of at least one HDACI such as OKI-179, largazole or OKI-5 as described herein. In another aspect the present invention provides a method for treating cancer in a subject in need thereof. In this preferred example, the method of the invention includes contacting a cancer cell with a therapeutically effective amount of an HDACI, and a PRDX6 inhibitor. In another aspect the present invention provides a method for treating cancer in a subject in need thereof. In this preferred example, the method of the invention includes contacting a cancer cell with a therapeutically effective amount of an a PRDX6 inhibitor. In another aspect the present invention provides pharmaceutical compositions for the treatment of cancer in a subject in need thereof. In this preferred example, the pharmaceutical compositions can include a therapeutically effective amount of an HDACI, such as OKI-179, largazole or OKI-5 as described herein, a Peroxiredoxin 6 (PRDX6) inhibitor, and a pharmaceutically acceptable carrier. In another aspect the present invention provides pharmaceutical compositions for the treatment of cancer in a subject in need thereof. In this preferred example, the pharmaceutical compositions can include a therapeutically effective amount of a PRDX6 inhibitor, and a pharmaceutically acceptable carrier. In another aspect the present invention provides compositions and methods for sensitizing a cancer cell to a programmed death-1 (PD1) and / or a programmed death ligand-1 (PD-L1) inhibitor. In this preferred example, the method can include contacting a cancer cell with a therapeutically effective amount of a Peroxiredoxin 6 (PRDX6) inhibitor, a histone deacetylase inhibitor (HDACI), or a combination of the same In another aspect the present invention provides compositions and method for sensitizing a cancer cell to a programmed death-1 (PD1) and / or a programmed death ligand-1 (PD-L1) inhibitor including a therapeutically effective amount of a PD1 inhibitor or a PD-L1 inhibitor, a Peroxiredoxin 6 (PRDX6) inhibitor, a histone deacetylase inhibitor (HDACI), and a pharmaceutically acceptable carrier which can be contacted with a cancer cell. In another aspect the present invention provides compositions and method for sensitizing a cancer cell to a programmed death-1 (PD1) and / or a programmed death ligand-1 (PD-L1) inhibitor including a therapeutically effective amount of Peroxiredoxin 6 (PRDX6) inhibitor, which can be contacted with a cancer cell. In another aspect the present invention provides method of treating cancer including the step of administering a therapeutically effective amount of a PD1 or PD-L1 inhibitor to a subject in need thereof, wherein the levels of Peroxiredoxin 6 (PRDX6) in the cancer cell of the subject are at a level, when compared to a reference level, indicative that the subject will respond to the administration of a therapeutically effective amount the a PD1 or PD-L1 inhibitor. In a preferred embodiment, the preferred level of PRDX6 is lower than a wild type level of PRDX6 from a reference level from a control sample. Additional aspects of the inventive technology will become apparent from the disclosure below. BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 Structure of OKI-179, prodrug of paragazole. Figure 2.1 Schematic of genome-scale lentiviral pooled screen. HCT116 cells expressing CRISPR-dCas9-VP64-GFP were infected with lentiviral sgRNA library. After puromycin selection, the cells were split into two sets: the first half was treated with DMSO, and second half was treated with 100 nM largazole. After treatment, cells were further lysed, and genomic DNA was extracted, digested and sequenced. Figure 2.2A-B Gene enrichment between cells treated with DMSO and largazole. (A) Each sgRNA was ranked using their absolute count in their genes’ names. (B) The analysis was performed by aggregating the read counts of all single guide RNAs (sgRNAs) per gene, followed by calculation of the fold change between largazole-treated and DMSO-treated groups. The p- value was used as a parameter to validate the results. A total of 202 genes (p-value < 2*10^-7) were identified as significantly enriched following treatment with largazole. Figure 2.3. GO enrichment analysis for 202 enriched genes. Both molecular functions and biological processes were executed and both functions and processes were ranked by -log10(p- value). Figure 2.4 Gene enrichment between cells treated with DMSO and largazole in secondary screen. sgRNAs were ranked by their total readings in their genes’ names. Figure 2.5 Validation of screen result using individual overexpression cell lines. (A) Cells overexpressing ASS1, PRDX6, PCDHB3, R3HDM2 and LRRK were treated with 100 nM largazole over 12 days. After treatment, cells were fixed with 4% formaldehyde in PBS and stained with 0.05% crystal violet.3 days DMSO treatment to wild-type cells was used as an indication of natural growth rate of HCT116 wild-type cells. (B) Crystal violet stained samples were solubilized with solubilization buffer (4:1:1, EtOH:MeOH:water) and absorbance was tested at 530 nm (n = 8). Data is represented as mean ± SD. Student’s t-test was used for statistical analysis for data. *p < 0.05, **p < 0.01, ***p < 0.001, ****p < 0.0001. Figure 2.6 Western blot for pan-H4ac, H3K9ac and H3K27ac expression levels in HCT116 wild-type and ASS1, PRDX6 overexpression cell lines. Cells were treated with largazole under indicated concentration for 2 hours. GAPDH was used as loading control. Figure 2.7A-D PRDX6 is a HDAC-independent target for largazole. (A) Western blot for PRDX6 knockdown and WT, S32A, C47S and S32A+C47S rescue validation. GAPDH was used as loading control. (B) Largazole sensitivity test for PRDX6 knockdown and different rescues. Cells with PRDX6 knockdown and PRDX6 knockdown plus either WT, S32A, C47S or S32A+C47S rescues were treated with 100 nM largazole over 12 days and cells were fixed with 4% formaldehyde in PBS and stained with 0.05% crystal violet.3 days DMSO treatment to wild- type cells was used as an indication of natural growth rate of HCT116 wild-type cells. (C) Quantification of (B). n = 8, Data is represented as mean ± SD. Student’s t-test was used for statistical analysis for data. *p < 0.05, **p < 0.01, ***p < 0.001. (D) Western blot for pan-H4ac expression levels in HCT116 WT, PRDX6 KD, PRDX6 KD + WT rescue, PRDX6 KD + S32A rescue, PRDX6 KD + C47S rescue, PRDX6 KD + S32A + C47S rescue cell lines. Cells were treated with 100nM largazole for 2 hours. GAPDH was used as loading control. Figure 2.8A-E Validation of PRDX6 induced largazole sensitization is functional dependent. (A) Schematic of combination treatment design.3*105 HCT116 cells were seeded into each well of 6-well plates. All wells were treated with 100 nM largazole for 6 days. After 6 days, cells were washed with PBS and refilled with either 100 nM largazole, 10 μM MJ33 or 100 nM largazole + 10 μM MJ33 for 3 days. Finally, cells were fixed with 4% formaldehyde in PBS and stained with 0.05% crystal violet. (B) Result and qualification of (A). n = 8, Data is represented as mean ± SD. Student’s t-test was used for statistical analysis for data. *p < 0.05, **p < 0.01, ***p < 0.001. (D-E) Growth inhibition of MJ33. 3*105 of HCT116 WT cells were seeded into each well of 6-well plate. All wells were treated with either DMSO or 10 μM MJ33 for 3 days. Finally, cells were fixed, stained, resolubilized and quantified. n = 8, Data is represented as mean ± SD. Student’s t-test was used for statistical analysis for data. *p < 0.05, **p < 0.01, ***p < 0.001. Figure 3.1A-D ATAC-seq reveals increased chromatin accessibility in PRDX6 knockdown cells after largazole treatment. Largazole promotes chromatin arrestment at discrete active promoters and enhancers that are characterized by the presence of the SP1 binding motif and its occupancy. MA plots illustrating significant changes in chromatin accessibility (blue) and at super-enhancers (green) resulting from two biological replicates using either (A) wild-type or (C) PRDX6-KD HCT116 cells treated with 100 nM largazole for 12 h. Chromatin states were determined using publicly available ChIP-seq (n = 10) and GRO-seq (n=1) data gathered from HCT116 cells grown under basal conditions. A hidden Markov model (ChromHMM) was implemented to assign the state categories (n=11) based on the combinations of chromatin marks and the frequency at which a given mark occurs at the given state. The genomic locations found within the chromatin states were used to determine the enrichment of largazole-induced higher chromatin accessibility or induced chromatin arrestment in either (B) wild-type or (D) PRDX6- KD HCT116 largazole-treated cells. Figure 3.2A-D TFEA analysis of ATAC-seq data reveals strong enrichment SP1 accessibility in PRDX6 knockdown cells with largazole treatment. (A, B) MA plots illustrate the transcription factors (TF) predicted to be the drivers of largazole-induced higher chromatin accessibility or repression as determined by ATAC-seq. Each data point represents the predicted activity score for a given TF with significant changes highlighted in red. ATAC-seq peaks from each condition were used to predict the activity score for transcription factors and the significant changes are highlighted in red. YY1 and SP1 DNA binding motif overrepresentation along the determined ATAC-seq peaks resulting from either (C) wild-type or (D) PRDX6-KD HCT116 cells treated with 100 nM largazole for 12 h. Figure 3.3A-D SP1 ChIP-seq reveals the mechanistic action of PRDX6 induced sensitization of largazole. (A, B) Scatter plots illustrating changes in SP1 chromatin occupancy by ChIP-seq using either wild-type or PRDX6-KD HCT116 cells treated with 100 nM largazole for 12 hours. Each data point represents a SP1 ChIP-seq peak with significant changes highlighted in blue and in green for super-enhancers. (C, D) Scatter plot illustrating the abundance of the DNA binding motif for either KLF3 (yellow), KLF4 (green), or other KLF family members (grey) within the SP1 ChIP-seq peaks significantly modified by largazole in wild-type or PRDX6-KD HCT116 cells. Figure 3.4A-B Western blot for SP1, KLF3, KLF4 and KLF15 expression levels in both wild-type and knockdown cell lines upon largazole treatment. (A) Both cell lines were treated with 100 nM of largazole by the indicated time period. GAPDH was used as loading control. (B) Both cell lines were treated with 100 nM of largazole by the indicated time period. Beta-actin was used as loading control. Figure 3.5A-B scRNA-seq reveals similarity between naïve and largazole resistant cells. (A) UMAP cluster plot represents similarity between naïve and resistant cells. Cells are stratified by condition, numeric labels are used to identify each cluster. (B) Numbers of genes that were upregulated in resistant cells more than 0.25-fold in each cluster. Clusters with more than 100 genes were shown as 100 limit. Figure 4.1 RT-qPCR of SP1 and PRDX6 for wild-type and PRDX6 knockdown cells upon largazole treatment. Cells were treated with 100 nM largazole and collected at indicated time point. RNA was extracted using Trizol ® method and real-time PCR was performed using Luna® universal qPCR master mix and mRNA levels were normalized using mRNA level of TATA binding protein (TBP). Figure 4.2 Structures of largazole and paragazole. The difference between largazole and paragazole was labeled in red. Figure 4.3A-C Microscale thermophoresis indicates interaction between SP1 and paragazole thiol. (A) Fluorescent-labeled SP1 was mixed with DMSO or pargazole thiol for 5 minutes. (B) SP1 was first mixed with DMSO + hydrogen peroxide or paragazole thiol + peroxide for 5 hours in dark, then both mixtures were labeled with fluorescent. (C) Both samples from (B) were retrieved and 5 mM DTT was added into both mixtures for 5 minutes under room temperature. All samples from (A) (B) (C) were loaded into capillaries and thermophoresis of fluorescent was tracked for each sample. (n=3) Figure 4.4A-C Microscale thermophoresis indicates the interaction between SP1 and paragazole thiol will not interfere the DNA binding ability of SP1. (A) Fluorescent-labeled SP1 was mixed with water or oligo for 5 minutes. (B) Samples from (A) were retrieved and same amount of paragazole thiol was added into both samples for 5 minutes. (C) SP1 was first mixed with DMSO + hydrogen peroxide or paragazole thiol + peroxide for 5 hours in dark, then both mixtures were labeled with fluorescent and were mixed with either water or oligo for 5 minutes. All samples from (A) (B) (C) were loaded into capillaries and thermophoresis of fluorescent was tracked for each sample. (n=3) Figure 4.5A-C Microscale thermophoresis indicates interaction between PRDX6 and paragazole thiol. (A) Fluorescent-labeled PRDX6 was mixed with DMSO or pargazole thiol for 5 minutes. (B) PRDX6 was first mixed with DMSO + hydrogen peroxide or paragazole thiol + peroxide for 5 hours in dark, then both mixtures were labeled with fluorescent. (C) Both samples from (B) were retrieved and 5 mM DTT was added into both mixtures for 5 minutes under room temperature. All samples from (A) (B) (C) were loaded into capillaries and thermophoresis of fluorescent was tracked for each sample. (n=3) Figure 4.6A-D Functional assay for PRDX6 GPx activity verified the conjugation of PRDX6 and pargazole thiol. (A) Purified PRDX6 GPx activity measured with assay. 4 μg of purified PRDX6 protein or same amount of phosphate buffer was mixed with 4 μL of 10 mM hydrogen peroxide and filled with phosphate buffer up to 20 μL. Amount of hydrogen peroxide was quantified as absorbance. (n=3) (B) PRDX6 GPx activity with paragazole or paragazole thiol. Samples with PRDX6 and without PRDX6 were prepared as (A), paragazole and paragazole thiol were prepared in serial-diluted manner. (n=3). (C) Normalized consumption of hydrogen peroxide showed increased consumption of hydrogen peroxide with largazole thiol. OD readings at 0 pmole of paragazole and paragazole thiol in (B) were used to normalize the data. (D) Proposed mechanism of reaction of paragazole thiol in PRDX6 GPx recycle reaction. The place where reaction happens was labeled in red. Figure 4.7A-B Mass spectrometry and in vivo evidence of PRDX6 paragazole conjugation. (A) Intact mass spectrometry of PRDX6 + DMSO and PRDX6 + pargazole thiol under oxidative environment. Peaks were labeled in red. (B) CESTA for HCT116 wild-type cells treatment with DMSO, MJ33, largazole and paragazole for 4 hours. 10 μM MJ33, 100 nM largazole, 1 μM largazole were used and 56 °C was labeled in red. Intensity of bands at 56°C were normalized with each treatment at 37°C. Figure 4.8 Schematic of mechanism of action of PRDX6 induced sensitization of largazole. PRDX6 protects SP1 from largazole in two ways: 1. the presence of PRDX6 decreases the chance of encounter for SP1 and largazole by conjugating itself with largazole. 2. PRDX6 decreases overall cellular oxidative stress which alleviates the conjugation for SP1 and largazole. Largazole conjugated SP1 degrades faster which increases the replacement from SP1 to KLFs which switches from genome-wide transcription activation to repression, and this leads to cell death eventually. Figure 5.1A-F IC50 assay of wild-type and PRDX6 knockdown in multiple cell lines. (A- F) Same number of cells were seeded into each well of 96-well plate. After incubation, DMEM was replaced with fresh DMEM with largazole in serial-diluted manner. Cells were washed, fixed, stained and quantified after 3 days treatment. Data is represented as mean ± SD. (n=4) Figure 5.2A-F IC50 assay of wild-type and PRDX6 knockdown in multiple HDAC inhibitors. (A-F) Same number of cells were seeded into each well of 96-well plate. After incubation, DMEM was replaced with fresh DMEM with largazole in serial-diluted manner. Cells were washed, fixed, stained and quantified after 3 days treatment. Data is represented as mean ± SD. (n=4) Figure 5.3A-B The difference of IC50 between largazole and paragazole is post- translational. (A) Real-time PCR result of largazole and pargazole. HCT116 wild-type cells were treated with 100 nM largazole or 1 μM paragazole for 48 hours. Total RNA of samples was extracted, and real-time PCR was performed. Data was quantified using 2^-ΔΔCT method and TATA binding protein (TBP) was used as housekeeping gene for quantification. (n=3) (B) Western blot analysis and quantification for all HDACis. HCT116 wild-type cells were treated with HDACis listed above using their IC50 concentrations obtained from table 5.2 for 48 hours. GAPDH was used as loading control. Intensity of PRDX6 bands was optimized using GAPDH bands and intensity of band for each treatment was further normalized using DMSO treatment by setting DMSO treated PRDX6 band as 1. (n=1) Figure 6.1A-I 5 years Kaplan-Meier curves of overall survival and disease-free survival in TCGA Patients stratified into High-Prdx6 and Low-Prdx6 groups based on median cutoff. Shaded area represents the 95% confidence interval. The log-rank test P<0.05 for all curves. (A- B) Pan-cancer. (C) Head and neck squamous carcinoma (HNSC). (D) Adrenocortical carcinoma (ACC). (E) Breast invasive carcinoma (BRCA). (F) Kidney renal papillary cell carcinoma (KIRP). (G) Brain lower grade glioma (LGG). (H) Lung adenocarcinoma (LUAD). (I) Uterine corpus endometrial carcinoma (UCEC). Figure 6.2 Overall survival analysis on groups of samples with significantly upregulated Prdx6 and significantly downregulated Prdx6 in tumors. Figure 6.3A-C Natural proliferation test for A223 (A), TCh3 (B) and TAb2 (C). For each type of cell, 500 cells were seeded into each well of 96-well plate. After indicated duration of incubation, cells were fixed, and crystal violet staining was performed. The plates were solubilized, and absorbance was measured at 530 nm. n = 12, the data is represented as mean ± SD. 7.1 Western blot for pan-AcH4, AcH3K9, AcH3K27 and AcH4K8 expression levels in HCT116 WT and ASS1, PRDX6, PCDHB3, PCEDH1B, R3HDM2 overexpression cell lines. Cells were treated with 100 nM largazole for 2 hours. GAPDH was used as loading control. Figure 7.2A-B. Expression Level of PRDX6 Alters Cells’ Sensitivity to Largazole While not Effecting Largazole HDACi Function. (A) Largazole sensitivity test for ASS1 knockdown and ASS1, PRDX6 overexpression cell lines. Cells with ASS1 knockdown and ASS1, PRDX6 overexpression were treated with 100 nM largazole over 12 days and cells were fixed with 4% formaldehyde in PBS and stained with 0.05% crystal violet. Figure 7.3A-B. (A) Western blot for ASS1, PRDX6 overexpression and ASS1 knockdown validation. GAPDH was used as loading control. (B) Natural growth rate for HCT116 WT cell lines. 3*105 of cells were seeded into one well of 6-well plate with DMSO treated along others stated in Figure 2A, cells were fixed stained after 3 days reaching 100% confluence. Figure. 8 AA223 WT or PRDX6KD cells were implanted in the flank of WTB6 mice. After tumor volume reached ~180 mm3(A223 WT recipient mice were treated from day 12 onwards and PRDX6KD recipient mice were treated from day 16 onwards) , animals were treated with 60mg / Kg OKI-179 or vehicle via oral gavage at 2 days interval for 9 doses. Tumor volume was measured and groups were compared on day 34. WT A223 n=13; WT A223+OKI-179, n=14; PRDX6KD A223, n=19; PRDX6KD A223+OKI-179, n=23. ***p<0.001, ****p<0.0001 Figure 9A-C. Animal experiment-Cohort-1: Check combination of anti-PD-L1 + OKI-179 in A223 PRDX6 KD cell line. (A) A223 PRDX6KD cells were implanted in the flank of WTB6 mice and after tumor volume reached ~180 mm3(day 16) tumor bearing mice were randomized into 4 groups, Control (n=8), OKI-179 (60 mg / kg / dose / 2 days via oral gavage for 9 doses, n=9), anti-PD-L1 (200 µg / mouse / 2days, i.p. , for 3 doses, n=10), and OKI-179+anti-PD-L1 combination (n=10). Tumor volume was measured and groups were compared on day 40. **p<0.01, ***p<0.001, ****p<0.0001. (B) Realtive change in tumor volume [(TVday34– TVday16) / TVday16] was calculated and compared for different treatment groups on day 34. (C) Based on the RCTV values on day 34 , different treatment recepients were divided into Responders (R, RCTV<0), Slow progressors (SP, 0<RCTV≤1.5) Non-responders (NR, RCTV>1.5). Percentage of each response group in different treatment regimens is indicated in the table. (D) Kaplan-Meier survival curve of A223 PRDX6KD tumor bearing recipient mice in different treatment groups. When tumor size reached 2 cm in any dimension or other humane end points were met, mice were euthanized in accordance with the institutional guidelines. *p<0.05, **p<0.01, ***p<0.001. Figure 10. Treatment cohorts across three treatment groups (R, SP, and NR) receiving: A223 with OKI-179, A233 with aPD-L1, A223 PRDX6 KD with OKI-179, A223 PRDX6 KD with aPD-L1, A223 with OKI-179 with anti-PD-L1, and aPD-L1, A223 PRDX6 KD with OKI-179 with aPD-L1. Figure 11A-B. Shows the percentage of recipients of treatments shown in Figure 10. (B) Breakdown of treatment cohorts across three treatment groups (R, SP, and NR). Figure 12A-B. Treating A223 vs A223 PRDX6 KD with OKI-005 (in-vitro prodrug of OKI-179) to see any upregulation of (A) PD-L1, and (C) MHCII. Figure 13A-B. Knockdown PRDX6 sensitizes colon cancer cells to OKI-5 treatment. n=3. *** p<0.01 by the t-test. (B) PRDX6 inhibitor MJ33 sensitize cells to largazole. Figure 14 Depletion of PRDX6 inhibits A223 tumor growth. WT and PRDX6KD cells were implanted in the flank of B6 mice. Tumor volume (mm3) vs days of the study is plotted. WT n=5; PRDX6KD n=6. Figure 15A-B. Depletion of PRDX6 enhances tumor growth inhibition by OKI-179. WT (A) and PRDX6KD cells (B) were implanted in the flank of B6 mice. After tumor volume reached 180 mm3, animals were dosed with 60mg / Kg OKI-179 or vehicle via oral gavage at 2 days. Tumor size was measured and plotted. WT A223 n=3; WT A223+OKI-179, n=4; PRDX6KD A223, n=4; PRDX6KD A223+OKI-179, n=5. *p<0.01. Figure 16A-B. Depletion of PRDX6 increases survival of mice bearing A223 tumors treated with OKI-179. Kaplan-Meier curve of recipient mice inoculated with A223 or A223 PRDX6KD cells. When tumor size reached 2cm in any dimension or other humane end points were met. Figure 17A-B. mIHC analysis of wild type and PRDX6-KD tumors treated with or without OKI-179. Sectioned formalin-fixed paraffin-embedded (FFPE) tumor tissues from the four indicated treatment groups on the same FFPE tissue slides were stained with antibodies against (A) PRDX6 or CD11b with DAPI. (B) Overlapping staining CD4, CD8, CD3 and DAPI. Figure 18A. OKI-5 upregulates the expression of MHC and class II expression more potently in A223-PRDX6-KD tumors. On day -1, A223 or A223-PRDX6-KD tumor cells were seeded (50,000 cells / well) in duplicate wells. On day 0, different concentration of OKI-005 was added to the cell culture and cells were treated for 48 hrs. On day 2, cells were harvested and analyzed by flow cytometry. MFI: mean fluorescent intensity. Representative flow plots and the normalized MFI are shown calculated by dividing the MFI of each sample with the MFI of corresponding control sample (without treatment). Figure 19A-C. OKI-5 upregulates the expression of PD-L1 expression more potently in A223-PRDX6-KD tumors. On day -1, A223 or A223-PRDX6-KD tumor cells were seeded (50,000 cells / well) in duplicate wells. On day 0, different concentration of OKI-5 was added to the cell culture and cells were treated for 48 hrs. On day 2, cells were harvested and analyzed by flow cytometry. MFI: mean fluorescent intensity. (A)The normalized MFI and representative flow plots (B) and (C) are shown calculated by dividing the MFI of each sample with the MFI of corresponding control sample. Figure 20. Effects of HDACi on CD8 T cell proliferation. T cells were isolated from WT C57BL / 6 mice, labeled with CFSE and stimulated with anti-CD3 / anti-CD28 beads in culture for 3 days. CFSE is a dye that is diluted once T cells proliferate, thus, the level of T cell proliferation is indicated by the extent of CFSE dilution. No dilution was seen with high panobinostat. Figure 21. Dose-dependent suppression of PRDX6 by chemically synthesized siRNA duplex (SEQ ID NO.9). Western blotting analysis of PRDX6 levels in MiaPaCa cells. Actin was used as a loading control. Figure 22A-B. PRDX6 knockdown decreases GSH (reduced glutathione) and GSSG (oxidised glutathione) levels in HTC116 and A223 cell lines. (A) shows GHS concentration in HCT116 cell line under control and with PRDX6 knock-down; (B) shows GHS concentration in HCT116 cell line under control and with PRDX6 knock-down and treatment with largazole; (C) shows ratio of GSH / GSSG in control and PRDX6 knock-down. As shown in the figures, largazole does not lower GSH or GSSG in WT type cells but decrease both PRDX6 knock-down cells, suggesting PRDX6 cannot restore GSH levels and that GSSG may be exported upon treatment with largazole. Figure 23A-C. (A-C) Actin glutathionylation decreased in response to PRDX6 depletion or treatment with largazole. Figure 24: Shows siRNA knockdown (KD) of PRDX6 mRNA (SEQ ID NO. 6) via treatment with Pan PRDX6 siRNA (SEQ ID NO.7) and hpPRDX6 siRNA (SEQ ID NO.8), at 10 and 100 nM. DETAILED DESCRIPTION OF THE INVENTION This present invention provides methods and materials involved in assessing samples (e.g., cancer cells) for the status of biomarkers indicative of cancer patient response to anti-cancer therapeutic regimens. In general, an analysis of the PRDX6 biomarker can reveal whether a cancer cell is likely sensitive or resistant to treatment with certain anti-cancer compounds, namely HDACi. Thus, the present invention is generally related to the identification of cancer patients that are predicted to benefit from the therapeutic administration of a HDACi anti-cancer compound. As used herein, the term “PRDX6” refers to peroxiredoxin-6, a protein belonging to the peroxiredoxin family of antioxidant enzymes. PRDX6 is a bifunctional enzyme with glutathione peroxidase activity (GPx) and Ca2+-independent phospholipase A2 (iPLA2) activity, has a higher expression in various cancer cells, which leads to the increase of antioxidant properties and promotes tumorigenesis. As used herein, “PRDX6 inhibitor” refers to any molecule that partially or fully inhibits the activity of PRDX6, or causes the depletion of PRDX6 in a cell. A PRDX6 inhibitor may specifically inhibit PRDX6 or may inhibit the activity of other proteins in addition to PRDX6. The terms and “PD1” refer herein to a native sequence “Programmed Death-1 receptor” polypeptide, polypeptide variants and fragments of a native sequence polypeptide and polypeptide variants (which are further defined herein). The PD-L1 polypeptide described herein may be that which is isolated from a variety of sources, such as from human tissue types or from another source, or prepared by recombinant or synthetic methods. As further used herein, “PD1” or “programmed death 1” refers to a cell surface receptor that suppresses T cell inflammatory responses. PD1 serves as an immune system checkpoint and prevents against development of autoimmune diseases. Anti-PD1 therapies are used in cancer to stimulate the immune system. The sequences of PD1 expression products are known for a number of species, e.g., human PD1 (NCBI Gene ID No: 5133) mRNA (NCBI Ref Seq: NM_005018.2) and polypeptide (NCBI Ref Seq: NP_005009.2). In one embodiment, the term “PD1”, or “PD-1” refers to the human protein PD1 (SEQ ID NO: 3) (protein without signal sequence) / (SEQ ID NO: 4)( protein with signal sequence) or a sequence having between 70 to 99% sequence homology to SEQ ID NO.3 or 4. Also referred to as PDCD1. As used herein, “PD1 inhibitor” refers to any molecule that partially or fully inhibits the activity of PD1, or causes the depletion of PD1 in a cell. A PD1 inhibitor may specifically inhibit PD1 or may inhibit the activity of other proteins in addition to PD1. For example, PD1 inhibitors may also inhibit the activity of other immune checkpoint molecules. The terms and “PD-L1” refer herein to a native sequence “Programmed Death Ligand 1” polypeptide, polypeptide variants and fragments of a native sequence polypeptide and polypeptide variants (which are further defined herein). The PD-L1 polypeptide described herein may be that which is isolated from a variety of sources, such as from human tissue types or from another source, or prepared by recombinant or synthetic methods. A “native sequence PD-L1 polypeptide” comprises a polypeptide having the same amino acid sequence as the corresponding PD-L1 polypeptide according to SEQ ID NO. 5, or a sequence having between 70 to 99% sequence homology to SEQ ID NO.3. As used herein, “PD1-L inhibitor” refers to any molecule that partially or fully inhibits the activity of PD-L1, or causes the depletion of PD-L1 in a cell. A PD1 inhibitor may specifically inhibit PD1 or may inhibit the activity of other proteins in addition to PD1. For example, PD1 inhibitors may also inhibit the activity of other immune checkpoint molecules. As used herein, reference to peptide or amino acid sequence, such as PDRX6, PD1, and PD-L1 specifically encompasses variations thereof. A variant, as defined herein includes a peptide having at least about 80% amino acid sequence identity with any of the native sequence. Ordinarily, polypeptide variant will have at least about 80% amino acid sequence identity, alternatively at least about 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% amino acid sequence identity, to a native sequence as disclosed herein. As used herein, reference to peptide or amino acid sequence, such as PDRX6, PD1, and PD-L1 specifically encompasses fragments thereof. A fragment includes a partial sequence of the amino acid sequence that retains the proteins functionality. For example, in one embodiment a fragment can include one or multiple peptide domain or portions thereof. As used herein, a biological marker (“biomarker” or “marker” or “pharmacodynamic biomarker”) is a characteristic that is objectively measured and evaluated as an indicator of normal biologic processes, pathogenic processes, or pharmacological responses to therapeutic interventions, consistent with NIH Biomarker Definitions Working Group (1998). Markers can be individual genes, or genome-wide markers, or individual residues of a protein, such as a histone residue that may be chemically modified, such as through acetylation and deacetylation. Markers can also include patterns or ensembles of characteristics indicative of particular biological processes. Markers can also include patterns or ensembles of characteristics indicative of dose- dependent biological processes. The biomarker measurement can increase or decrease (“modulate”) to indicate a particular biological event or process. In addition, if the biomarker measurement typically changes in the absence of a particular biological process, a constant measurement can indicate occurrence of that process. Anti-PRDX6 antibodies are commercially available through multiple companies, such as ThermoFisher®, Proteintech®, and Biotechne® (which are incorporated herein by reference). A biomarker of this invention may be used for diagnostic and prognostic purposes, as well as for therapeutic, drug screening and patient stratification purposes (e.g., to group patients into a number of “subsets for evaluation”), as well as other purposes described herein. Further included is information related to the function of the gene and the biological process that it is involved in. The polynucleotide sequences of these genes, as well as the sequences of the polypeptides encoded by them, expression levels, chemical modifications, and epigenetic modifications, are publicly available and known to one having average skill in the art. All information associated with the publicly-available identifiers and accession numbers, including the nucleic acid sequences of the associated genes and the amino acid sequences of the encoded proteins is incorporated herein by reference in its entirety. The present invention includes all compositions and methods relying on correlations between the biomarker PRDX6, and HDACIs (sensitivity and / or resistance) in cancer cells. Such methods include determining whether a cancer patient is predicted to respond to administration of a certain single, or combination of therapies, as well as methods for assessing the efficacy of such therapy, and preferably a HDACI or inhibitor or PRDX6, or the co-administration of the same. Further included are methods for improving the efficacy of a cancer therapy by administering to a subject a therapeutically effective amount of one or more HDACIs, such as largazole and / or paragazole and their analogs, and a PRDX6 inhibitor. The term “administered” or “administering,” as used herein, refers to any method of providing a composition to a patient such that the composition has its intended effect on the patient. An exemplary method of administering is by a direct mechanism such as, local tissue administration (i.e., for example, extravascular placement), oral ingestion, transdermal patch, topical, inhalation, suppository etc. In this context, the term “effective” or “effective amount” or “therapeutically effective amount” is to be understood broadly to include reducing or alleviating the signs or symptoms of cancer, improving the clinical course of the disease, or reducing any other objective or subjective indicia of the disease, or inducing an observable effect, such a modulations in transcription of mRNA processing and the like. Different drugs, doses and delivery routes can be evaluated by performing the method using different drug administration conditions. Toxicity and therapeutic efficacy of such compositions can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e.g., for determining the LD50 (the dose lethal to 50% of the population) and the ED50 (the dose therapeutically effective in 50% of the population). The dose ratio between toxic and therapeutic effects is the therapeutic index, and it can be expressed as the ratio LD50 / ED50. Compounds that exhibit large therapeutic indices are preferred. The data obtained from these cell culture assays and additional animal studies can be used in formulating a range of dosage for human use. The dosage of such compounds lies preferably within a range of circulating concentrations that include the ED50with little or no toxicity. The dosage varies within this range depending upon the dosage form employed, sensitivity of the patient, and the route of administration. In any of the embodiments of the present invention, the HDAC inhibitor can include, but is not limited to, any compound or its analog that inhibits the function or activity of a histone deacetylases. HDAC inhibitors can include, hydroxamic acid, a carboxylic acid, a benzamide, an epoxide, a short- chain fatty acid, a cyclic tetrapeptide containing a 2-amino-8-oxo-9, 10-epoxy- decanoyl moiety, and a cyclic peptide without the 2-amino-8-oxo-9, 10-epoxy-decanoyl moiety. A hydroxamic acid can include, but is not limited to, suberoylanilidine hydroxamic acid, TSA, and SAHA. A carboxylic acid can include, but is not limited to, butanoic acid, valproic acid, and 4- phenylbutanoic acid. A benzamide can include, but is not limited to, N- acetyldinaline and MS- 275. An epoxide can include, but is not limited to, trapoxin, depeudecin, and depsipeptide FK 228. Additional embodiments, and HDACi can include In a preferred embodiment, the HDAC inhibitor is largazole. In another preferred embodiment, HDAC inhibitor comprises the macrocyclic compounds described in US Pat. App. No.13 / 700,373, entitled “Macrocyclic Compounds Useful As Inhibitors of Histone Deacetylases.” (Each compound disclosed in that application, in particular all macrocyclic compounds disclosed in figures 1-7, paragraphs 14-73 and claims 20-33. In addition, each compound disclosed in claims 1-11 of US Pat. No.8754050, and claims 1-15 of US Pat. No.9422340, all of which are specifically incorporated herein by reference and may generally be referred to as ONK101 or paragazole.) In a preferred embodiment, the HDAC inhibitor is one or more of the following: Vorinostat, Romidepsin (Isodax), SAHA (Vironostat), PDX101 (Belinostat), Panobinostat, Eintinostat, TSA (Trichostatin), ONK101(Paragazole), Largazole, Entinostat, and chidamide (CS055). One embodiment of the present invention provides methods related to predicting a cancer patient's response to a cancer treatment regimen comprising an HDACi, using the expression levels of the functional biomarker PRDX6 identified by the inventors as correlated with a cancer patient’s likelihood of response (or lack of response) to the an HDACi. These expression levels may be assessed at the genetic levels (mRNA, including increased transcription, gene duplication / amplification, polysomy, prolonged mRNA transcript half-life, mutations that lead to gain of function, loss of function, or increased or decreased transcription, etc.) and at the protein levels (protein content, protein activity, gain of function or loss of function mutations, prolonged protein half-life, post translational modifications, etc.). As used here “suppression” or “inhibition” or “depletion” are used interchangeably to denote the down-regulation of the expression of the product of a target sequence relative to its normal expression level in a wild type environment. Suppression includes expression that is decreased by about 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% relative to the wild type expression level. One embodiment of the present invention includes a method of determining the expression level of PRDX6 in a cancer cell from a cancer patient. As described herein, high levels, or overexpression of PRDX6 can be correlated with HDACi resistant, while low or depleted levels of PRDX6 can be correlated with HDACi sensitivity. In this embodiment, the level of the biomarker is then correlated with an increased likelihood that the cancer patient will respond to the cancer treatment regimen comprising an HDACi anti-cancer agent. Another embodiment of this aspect of the disclosure is a method that includes determining, in a cancer cell from the cancer patient, the expression level of the biomarker PRDX6. The level of PRDX6 that is greater than a reference number may then be correlated with an increased likelihood that the cancer patient will not respond to a treatment regimen including an HDACi anti-cancer agent. Similarly, the level of the biomarker PRDX6 that is lower than a reference number may then be correlated with an increased likelihood that the cancer patient will respond to a treatment regimen including an HDACi anti-cancer agent. Another embodiment of this aspect of the disclosure is a method that includes determining, in a cancer cell from a cancer patient or genomic DNA obtained therefrom, the level of PRDX6, and administering to the cancer patient a cancer treatment regimen comprising a HDACi anti- cancer agent, if the PRDX6 biomarker expression level is similar to a reference number associated with HDACi sensitivity to the biomarker expression level. Another embodiment of this aspect of the disclosure is a method that includes selecting a patient for treatment with an anti-cancer agent on the basis of the patient having, in a cancer cell, the level of PRDX6 biomarker, and selectively administering a HDACi anti-cancer agent to the patient, and preferably OKI-179, largazole, and OKI-5, or a combination of the same. Another embodiment of this aspect of the disclosure is a method that includes selecting a patient for treatment with an anti-cancer agent on the basis of the patient having, in a cancer cell, the level of PRDX6 biomarker, and selectively administering a HDACi anti-cancer agent to the patient, and preferably a HDACi is selected from: Vorinostat, Romidepsin (Isodax), SAHA (Vironostat), PDX101 (Belinostat), Panobinostat, Eintinostat, TSA (Trichostatin), OKI-5 (Paragazole), Largazole, OKI-179, and chidamide (CS055), or a combination of the same. In certain embodiments, the level of PRDX6 biomarker is detected by a method selected from Western blot, immunoblot, enzyme-linked immunosorbant assay (ELISA), radioimmunoassay (RIA), immunoprecipitation, surface plasmon resonance, chemiluminescence, fluorescent polarization, phosphorescence, immunohistochemical analysis, matrix-assisted laser desorption / ionization time-of-flight (MALDI-TOF) mass spectrometry, microcytometry, microarray, microscopy, fluorescence activated cell sorting (FACS), and flow cytometry. In some embodiments, the biomarker is detected by immunohistochemical (IHC) analysis. Another aspect of this disclosure provides assay kits for selecting a cancer patient who is predicted to benefit or not to benefit from therapeutic administration of a HDACi anticancer compound. These assay kits include a means for detecting, in a sample of cancer cells, a level of PRDX6 biomarker. These assay kits also include a means for detecting, in the sample of cancer cells, a control selected from a control sample for detecting sensitivity to the HDACi anticancer compound, a control sample for detecting resistance to the HDACi anticancer compound. These assay kits also include information containing a predetermined control level of the PRDX6 biomarker that has been correlated with sensitivity or resistance to the HDACi anticancer compound, and information containing a predetermined control level of the PRDX6 biomarker that has been correlated with resistance to the anticancer compound. In these assay kits, the means for detecting the biomarkers may include a nucleotide probe that hybridizes to a portion of the PRDX6 biomarker. Alternatively or additionally, in these assay kits, the means for detecting PRDX6 biomarker may include a detectable label. In certain embodiments, in these assay kits the means for detecting is immobilized on a substrate. Suitable methods of obtaining a cell sample from a patient are known to a person of skill in the art. A patient sample can include any bodily fluid or tissue from a patient that may contain cancer cells or proteins of cancer cells. More specifically, according to the present invention, the term “test sample” or “patient sample” can be used generally to refer to a sample of any type which contains cells or products that have been secreted from cells to be evaluated by the present method, including but not limited to, a sample of isolated cells, a tissue sample and / or a bodily fluid sample. Most typically in the present invention, the sample is a tissue sample. According to the present invention, a sample of cancer cells is a specimen of cells, typically in suspension or separated from connective tissue which may have connected the cells within a tissue in vivo, which have been collected from an organ, tissue or fluid by any suitable method which results in the collection of a suitable number of cells for evaluation by the method of the present invention. The cells in the cell sample are not necessarily of the same type, although purification methods can be used to enrich for the type of cells that are preferably evaluated. Cells can be obtained, for example, by scraping of a tissue, processing of a tissue sample to release individual cells, or isolation from a bodily fluid. A tissue sample, although similar to a sample of isolated cells, is defined herein as a section of an organ or tissue of the body which typically includes several cell types and / or cytoskeletal structure which holds the cells together. One of skill in the art will appreciate that the term “tissue sample” may be used, in some instances, interchangeably with a “cell sample”, although it is preferably used to designate a more complex structure than a cell sample. A tissue sample can be obtained by a biopsy. A bodily fluid sample, like the tissue sample, contains the cells to be evaluated, and is a fluid obtained by any method suitable for the particular bodily fluid to be sampled. Bodily fluids suitable for sampling include, but are not limited to, blood, mucous, seminal fluid, saliva, sputum, bronchial lavage, breast milk, bile and urine. In general, the sample type (i.e., cell, tissue or bodily fluid) is selected based on the accessibility and structure of the organ or tissue to be evaluated for tumor cell growth and / or on what type of cancer is to be evaluated. For example, if the organ / tissue to be evaluated is the colon, the sample can be a sample of epithelial cells from a biopsy (i.e., a cell sample) or a colon tissue sample from a biopsy (a tissue sample). The present invention is particularly useful for evaluating patients with cancer that are sensitive or resistant to HDACi, or misregulation of the activity of SP1 transcription factor. In one method of the invention, the level of PRDX6 protein expression in the cancer cell sample is compared to a control level of that protein expression selected from: (i) a control level that has been correlated with sensitivity to a HDACi anticancer compound as described herein; and (ii) a control level that has been correlated with resistance to a HDACi anticancer compound of the invention. A patient is selected as being predicted to benefit from therapeutic administration of the HDACi compound of the invention, or a drug having substantially similar biological activity, if the level of protein expression in the patient's cancer cells is statistically similar to the control level of protein expression that has been correlated with sensitivity to the HDACi compound, or if the level of PRDX6 protein expression in the patient's cancer cells is statistically less than the level of that PRDX6 protein expression that has been correlated with resistance to the anticancer compound. A patient is predicted to not benefit from therapeutic administration of a HDACi anticancer compound of the invention, or a drug having substantially similar biological activity as an anticancer compound of the invention, if the level of PRDX6 expression in the patient's cancer cells is statistically similar to the control level of protein expression that has been correlated with resistance to a HDACi anticancer treatment, or if the level of PRDX6 protein expression in the patient's cancer cells is statistically more than the level of that PRDX6 protein expression that has been correlated with sensitivity to the anticancer compound. In another embodiment, the invention includes a method of assessing the efficacy or effectiveness of an HDACI inhibitor therapy treatment being administered to a cancer subject. In this preferred embodiment, the method can include the steps of measuring the activity level of a pharmacodynamic biomarker PRDX6 in a first sample obtained from the subject at a time t0. In this example, an HDACI and / or a PRDX6 inhibitor can be administered after said time t0. The activity level of the pharmacodynamic biomarker PRDX6 in a second sample obtained from the subject at time t1 can be measured, wherein a change in the activity level of the pharmacodynamic biomarker PRDX6 in the second sample relative to the first sample is an indication that the HDACI treatment is effective for treating cancer in the subject. In another embodiment, the invention includes a method of treating a subject having a cancer. In a preferred embodiment, the method can include determining the level of PRDX6 in: i) a test sample obtained from the subject, and ii) optionally a control sample. Next, an optional reference value can be obtained corresponding to a level of PRDX6, wherein the level of PRDX6 in the test sample relative to the control sample or the reference value indicates whether the subject will respond to the administration of a therapeutically effective amount of at least one HDACI; and, identifying the subject as having a cancer involving a level of PRDX6 indictive that the subject will respond to the HDACI based on the level of PRDX6 in the test sample, and administering an effective amount of a HDACI to the subject to treat the cancer, or identifying the subject as having the cancer not involving a level of PRDX6 indictive that the subject will not respond to the HDACI based on the level of PRDX6 in the test sample, and withholding the administration of the HDACI to the subject, and optionally, administering a cancer therapy other than the HDACI to the subject to treat the cancer. The control sample can be obtained from: a) an individual belonging to the same species as the subject and not having cancer, or b) an individual belonging to the same species as the subject and known to have a cancer having a level of PRDX6 indictive that the subject will respond to the HDACI, or c) an individual belonging to the same species as the subject and known to have a cancer having a level of PRDX6 indictive that the subject will not respond to the HDACI. According to the present invention, a “reference value” can correspond to a level of PRDX6 indictive that the subject will respond to the HDACI, or a level of PRDX6 indictive that the subject will not respond to the HDACI. According to the present invention, a “control level” is a control level of protein expression, which can include a level of PRDX6 expression that is correlated with sensitivity to the HDACi anticancer compounds of the invention or that is correlated with resistance to HDACi anticancer compounds of the invention. Therefore, it can be determined, as compared to the control or baseline level of PRDX6 protein expression, whether a patient sample is more likely to be sensitive to or resistant to the HDACi anticancer compound therapy (e.g., a good responder or responder (one who will benefit from the therapy), or a poor responder or non-responder (one who will not benefit or will have little benefit from the therapy)). The method for establishing a control level of expression is selected based on the sample type, the tissue or organ from which the sample is obtained, and the status of the patient to be evaluated. Preferably, the method is the same method that will be used to evaluate the sample in the patient. In a preferred embodiment, the PRDX6 control level is established using the same cell type as the cell to be evaluated. In a preferred embodiment, the PRDX6 control level is established from control samples that are from patients or cell lines known to be resistant or sensitive to a HDACi anticancer compound of the invention. In one aspect, the PRDX6 control samples are obtained from a population of matched individuals. According to the present invention, the phrase “matched individuals” refers to a matching of the control individuals on the basis of one or more characteristics which are suitable for the type of cell or tumor growth to be evaluated. For example, control individuals can be matched with the patient to be evaluated on the basis of gender, age, race, or any relevant biological or sociological factor that may affect the baseline of the control individuals and the patient (e.g., preexisting conditions, consumption of particular substances, levels of other biological or physiological factors). To establish a PRDX6 control level, samples from a number of matched individuals are obtained and evaluated in the same manner as for the test samples. The number of matched individuals from whom control samples must be obtained to establish a PRDX6 suitable control level (e.g., a population) can be determined by those of skill in the art, but should be statistically appropriate to establish a suitable baseline for comparison with the patient to be evaluated (i.e., the test patient). The values obtained from the control samples are statistically processed using any suitable method of statistical analysis to establish a suitable baseline level using methods standard in the art for establishing such values. It will be appreciated by those of skill in the art that a control level need not be established for each assay as the assay is performed but rather, a PRDX6 baseline or control can be established by referring to a form of stored information regarding a previously determined control level for sensitive and resistant patients (responders and non-responders), such as a control level established by any of the above-described methods. Such a form of stored information can include, for example, but is not limited to, a reference chart, listing or electronic file of population or individual data regarding sensitive and resistant tumors / patients, or any other source of data regarding control level that is useful for the patient to be evaluated. The steps of detection of the PRDX6 biomarker according to the present invention may be combined in many different combinations as described herein, and the steps can be performed in any order, or substantially simultaneously. Statistical analysis to determine differences between controls and patient samples can be performed using any methods known in the art, including, but not limited to, Fisher's exact test of Pearson's chi-square test for qualitative variables, and using Student's t test or analysis of variance for continuous variables. Statistical significance is typically defined as p<0.05. Once treated for a particular period of time (e.g., between one to six months), the patient can be assessed to determine whether or not the HDACi treatment regimen has an effect. If a beneficial effect is detected, the patient can continue with the same or a similar cancer treatment regimen. If a minimal or no beneficial effect is detected, then adjustments to the cancer treatment regimen can be made. For example, the dose, frequency of administration, or duration of treatment can be increased. In some cases, additional anti-cancer agents can be added to the treatment regimen, or a particular anti-cancer agent can be replaced with one or more different anti-cancer agents. The patient being treated can continue to be monitored as appropriate, and changes can be made to the cancer treatment regimen as appropriate. Another embodiment of the invention includes an assay kit for performing any of the methods of the present invention. The assay kit can include any one or more of the following components: (a) a means for detecting in a sample of cancer cells a level of expression of the PRDX6 gene and / or protein; (b) a means for detecting in a sample of tumor cells a level of expression or activity of SP1 transcription factor. The assay kit preferably also includes one or more controls. The controls could include: (i) a control sample for detecting sensitivity to the HDACi anticancer compounds of the invention being evaluated for use in a patient; (ii) a control sample for detecting resistance to the HDACi anticancer compounds of the invention; (iii) information containing a predetermined control level of the PRDX6 biomarker to be measured with regard to sensitivity or resistance to a HDACi anticancer compound of the invention (e.g., a predetermined control level of gene expression and / or protein expression that has been correlated with sensitivity to or resistance to the anticancer compound). In one embodiment, a means for detecting PRDX6 gene or protein expression can generally be any type of reagent that can be used in a method of the present invention. Such a means for detecting include, but are not limited to: a probe or primer(s) that hybridizes under stringent hybridization conditions to a PRDX6 gene. Additional reagents useful for performing an assay using such means for detection can also be included, such as reagents for performing in situ hybridization, reagents for detecting fluorescent markers, reagents for performing polymerase chain reaction, etc. In another embodiment, a means for detecting PRDX6 protein expression can generally be any type of reagent that can be used in a method of the present invention. Such a means for detection includes, but is not limited to, antibodies and antigen binding fragments thereof, peptides, binding partners, aptamers, enzymes, and small molecules. Additional reagents useful for performing an assay using such means for detection can also be included, such as reagents for performing immunohistochemistry or another binding assay. The means for detecting PRDX6 using the assay kit of the present invention can be conjugated to a detectable tag or detectable label. Such a tag can be any suitable tag which allows for detection of the reagents used to detect the gene or protein of interest and includes, but is not limited to, any composition or label detectable by spectroscopic, photochemical, electrical, optical or chemical means. Useful labels in the present invention include: biotin for staining with labeled streptavidin conjugate, magnetic beads (e.g., DYNABEADS™), fluorescent dyes (e.g., fluorescein, Texas red, rhodamine, green fluorescent protein, and the like), radiolabels (e.g., 3H, 125I, 35S, 14C, or 32P), enzymes (e.g., horse radish peroxidase, alkaline phosphatase and others commonly used in an ELISA), and colorimetric labels such as colloidal gold or colored glass or plastic (e.g., polystyrene, polypropylene, latex, etc.) beads. In addition, the means for detecting of the assay kit of the present invention can be immobilized on a substrate. Such a substrate can include any suitable substrate for immobilization of a detection reagent such as would be used in any of the previously described methods of detection. Briefly, a substrate suitable for immobilization of a means for detecting includes any solid support, such as any solid organic, biopolymer or inorganic support that can form a bond with the means for detecting without significantly affecting the activity and / or ability of the detection means to detect the desired target molecule. Exemplary organic solid supports include polymers such as polystyrene, nylon, phenol-formaldehyde resins, and acrylic copolymers (e.g., polyacrylamide). The kit can also include suitable reagents for the detection of the reagent and / or for the labeling of positive or negative controls, wash solutions, dilution buffers and the like. The kit can also include a set of written instructions for using the kit and interpreting the results. In another aspect the present invention provides a method for treating cancer in a subject in need thereof. In this preferred example, the method of the invention includes contacting a cancer cell in a subject, and preferably a human subject, with a therapeutically effective amount of an HDACI, and a PRDX6 inhibitor. In this preferred embodiment, the HDAI of the invention can be selected from: OKI-179, largazole, and OKI-5, or a combination of the same, and a PRDX6 inhibitor of the invention can be selected from: a small-inhibitory RNA (siRNA), short hairpin RNA (shRNA), bifunctional RNA, antisense oligonucleotide, anti-PRDX6 antibody or functional fragment thereof, ribozyme, deoxyribozyme, aptamer, small molecule or gene therapy that knocks out PRDX6. In another preferred embodiment, the HDACI of the invention can be selected from: Vorinostat, Romidepsin (Isodax), SAHA (Vironostat), PDX101 (Belinostat), Panobinostat, Eintinostat, TSA (Trichostatin), OKI-5 (Paragazole), Largazole, OKI-179, and chidamide (CS055), or a combination of the same, and a PRDX6 inhibitor can be selected from: a small- inhibitory RNA (siRNA), short hairpin RNA (shRNA), bifunctional RNA, antisense oligonucleotide, anti-PRDX6 antibody or functional fragment thereof, ribozyme, deoxyribozyme, aptamer, small molecule or gene therapy that knocks out PRDX6. In another aspect the present invention provides a method for treating cancer in a subject in need thereof. In this preferred example, the method of the invention includes administering a therapeutically effective amount of a HDACI to a subject in need thereof, and preferably a human subject, wherein the levels of PRDX6 in the cancer cell of the subject are at a level, when compared to a reference level, indicative that the subject will respond to the administration of a therapeutically effective amount the HDACI. In this preferred embodiment, the HDAI of the invention can be selected from: OKI-179, largazole, and OKI-5, or a combination of the same, and a PRDX6 inhibitor of the invention can be selected from: a small-inhibitory RNA (siRNA), short hairpin RNA (shRNA), bifunctional RNA, antisense oligonucleotide, anti-PRDX6 antibody or functional fragment thereof, ribozyme, deoxyribozyme, aptamer, small molecule or gene therapy that knocks out PRDX6. In another preferred embodiment, the HDACI of the invention can be selected from: Vorinostat, Romidepsin (Isodax), SAHA (Vironostat), PDX101 (Belinostat), Panobinostat, Eintinostat, TSA (Trichostatin), OKI-5 (Paragazole), Largazole, OKI-179, and chidamide (CS055), or a combination of the same, and a PRDX6 inhibitor can be selected from: a small-inhibitory RNA (siRNA), short hairpin RNA (shRNA), bifunctional RNA, antisense oligonucleotide, anti-PRDX6 antibody or functional fragment thereof, ribozyme, deoxyribozyme, aptamer, small molecule or gene therapy that knocks out PRDX6. In another aspect the present invention provides a method for treating cancer in a subject in need thereof. In this preferred example, the method of the invention includes contacting a cancer cell in a subject, and preferably a human subject, with a therapeutically effective amount of a PRDX6 inhibitor. In this preferred embodiment, the PRDX6 inhibitor of the invention can be selected from: a small-inhibitory RNA (siRNA), short hairpin RNA (shRNA), bifunctional RNA, antisense oligonucleotide, anti-PRDX6 antibody or functional fragment thereof, ribozyme, deoxyribozyme, aptamer, small molecule or gene therapy that knocks out PRDX6. The present invention further provides pharmaceutical compositions, as defined herein, and methods of making a pharmaceutical composition comprising admixing at least one histone deacetylase inhibitor (HDACI), as defined herein, and a PRDX6 inhibitor together with one or more pharmaceutically acceptable carriers, excipients, buffers, adjuvants, stabilizers, or other materials, as described herein. In a preferred embodiment, the HDACI of the pharmaceutical composition can be selected from: OKI-179, largazole, and OKI-5, or a combination of the same. In alternative embodiment, the HDACI of the pharmaceutical composition can be selected from: Vorinostat, Romidepsin (Isodax), SAHA (Vironostat), PDX101 (Belinostat), Panobinostat, Eintinostat, TSA (Trichostatin), OKI-5 (Paragazole), Largazole, OKI-179, and chidamide (CS055), or a combination of the same, and the PRDX6 inhibitor of the pharmaceutical composition can be selected from: a small-inhibitory RNA (siRNA), short hairpin RNA (shRNA), bifunctional RNA, antisense oligonucleotide, anti-PRDX6 antibody or functional fragment thereof, ribozyme, deoxyribozyme, aptamer, small molecule or gene therapy that knocks out PRDX6. The present invention further provides pharmaceutical compositions, as defined herein, and methods of making a pharmaceutical composition comprising admixing at least one PRDX6 inhibitor together with one or more pharmaceutically acceptable carriers, excipients, buffers, adjuvants, stabilizers, or other materials, as described herein. The PRDX6 inhibitor of the pharmaceutical composition can be selected from: a small-inhibitory RNA (siRNA), short hairpin RNA (shRNA), bifunctional RNA, antisense oligonucleotide, anti-PRDX6 antibody or functional fragment thereof, ribozyme, deoxyribozyme, aptamer, small molecule or gene therapy that knocks out PRDX6, MJ33, or an oligonucleotide according to SEQ ID NO’s.7-9. As used herein, “pharmaceutical compositions” are compositions that include an amount (for example, a unit dosage) of one or more of the disclosed compounds together with one or more non-toxic pharmaceutically acceptable additives, including carriers, diluents, and / or adjuvants, and optionally other biologically active ingredients. Such pharmaceutical compositions can be prepared by standard pharmaceutical formulation techniques such as those disclosed in Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pa. (l9th Edition). The pharmaceutical acceptable carrier may comprise any conventional pharmaceutical carrier or excipient. The choice of carrier and / or excipient will to a large extent depend on factors such as the particular mode of administration, the effect of the carrier or excipient on solubility and stability, and the nature of the dosage form. The term “pharmaceutically acceptable” as used herein pertains to compounds, materials, compositions, and / or dosage forms which are, within the scope of sound medical judgement, suitable for use in contact with the tissues of a subject (e.g., human) without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio. Each carrier, excipient, etc. must also be “acceptable” in the sense of being compatible with the other ingredients of the formulation. Suitable carriers, diluents, excipients, etc. can be found in standard pharmaceutical texts. See, for example, “Handbook of Pharmaceutical Additives”, 2nd Edition (eds. M. Ash and I. Ash), 2001 (Synapse Information Resources, Inc., Endicott, N.Y., USA), “Remington's Pharmaceutical Sciences”, 20th edition, pub. Lippincott, Williams & Wilkins, 2000; and “Handbook of Pharmaceutical Excipients”, 2nd edition, 1994. The formulations may conveniently be presented in unit dosage form and may be prepared by any methods well known in the art of pharmacy. Such methods include the step of bringing into association the active compound with the carrier which constitutes one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately bringing into association the active compound with liquid carriers or finely divided solid carriers or both, and then if necessary, shaping the product. Formulations may be in the form of liquids, solutions, suspensions, emulsions, elixirs, syrups, tablets, lozenges, granules, powders, capsules, cachets, pills, ampoules, suppositories, pessaries, ointments, gels, pastes, creams, sprays, mists, foams, lotions, oils, boluses, electuaries, or aerosols. The present invention includes all compositions and methods relying on correlations between the biomarker PRDX6, and PD1 or PD-L1 inhibitors (sensitivity and / or resistance) in cancer cells. Such methods include determining whether a cancer patient is predicted to respond to administration of a certain single, or combination of therapies, as well as methods for assessing the efficacy of such therapy, and preferably the administration of a PRDX6 inhibitor, the co- administration of a PD1 inhibitor and a PRDX6 inhibitor, as well as in other embodiments, the co- administration with a PD1 inhibitor, and a PRDX6 inhibitor HDACi, all of which can sensitize the cell to PD1 or PD-L1 inhibitors. The present invention includes methods for sensitizing a cancer cell to a sensitizing a cancer cell to a programmed death-1 (PD1) and / or a programmed death ligand-1 (PD-L) inhibitor. In a preferred embodiment, the method includes contacting a cancer cell with a therapeutically effective amount of a Peroxiredoxin 6 (PRDX6) inhibitor, which can preferably be combined with a pharmaceutically acceptable carrier to form a pharmaceutical composition. In additional embodiments, present invention includes methods for sensitizing a cancer cell to a Programmed death-1 (PD1) and / or a Programmed death ligand-1 (PD-L1) inhibitor. In a preferred embodiment, the method includes contacting a cancer cell with a therapeutically effective amount of a Peroxiredoxin 6 (PRDX6) inhibitor, a histone deacetylase inhibitor (HDACI), or a combination of the same. In certain other embodiments, the sensitized cell can further be contacted with a PD1 inhibitor or a PD-L1 inhibitor as a method of treating the cancer. In preferred embodiments, the aforementioned inhibitors can be incorporated with a pharmaceutically acceptable carrier to form a pharmaceutical composition. Exemplary PRDX6 inhibitors can be selected from: a small-inhibitory RNA (siRNA), short hairpin RNA (shRNA), bifunctional RNA, antisense oligonucleotide, anti-PRDX6 antibody or functional fragment thereof, ribozyme, deoxyribozyme, aptamer, small molecule or gene therapy that knocks out PRDX6. In a preferred embodiment, the PRDX6 inhibitors can include an inhibitory RNA oligonucleotide according to SEQ ID NO. SEQ ID NO’s.7-9. Exemplary HDACI can be selected from: Vorinostat, Romidepsin (Isodax), SAHA (Vironostat), PDX101 (Belinostat), Panobinostat, Eintinostat, TSA (Trichostatin), OKI-5 (Paragazole), Largazole, OKI-179, and chidamide (CS055), or a combination of the same. Exemplary PD1 inhibitors can be selected from: Pembrolizumab, Nivolumab, Cemiplimab, Toripalimab, Retifanlimab, Dostarlimab, a small-inhibitory RNA (siRNA), short hairpin RNA (shRNA), bifunctional RNA, antisense oligonucleotide, anti-PD1 antibody or functional fragment thereof, a ribozyme, a deoxyribozyme, or an aptamer. In addition, exemplary PD-L1 inhibitors can selected from: Atezolizumab, Avelumab, Durvalumab, a small-inhibitory RNA (siRNA), short hairpin RNA (shRNA), bifunctional RNA, antisense oligonucleotide, anti-PD-L1 antibody or functional fragment thereof, a ribozyme, a deoxyribozyme, or an aptamer. The subject having cancer is preferably a human, and the cancer can preferably be non- small cell lung cancer (NSCLC), but can further be selected from one or more of the following: Head and neck cancer; lung cancer; small cell lung cancer (SCLC); mediastinal neoplasms such as neurogenic tumors and mesenchymal tumors; gastrointestinal (GI) cancers such as esophagus, Cancers of the stomach (stomach cancer), pancreas, liver and bile ducts (including hepatocellular carcinoma (HCC)), and small and large intestine (including colorectal cancer); prostate cancer; testicular cancer; gynecological cancer, ovary cancer; breast cancer such as breast cancer, hormone receptor positive breast cancer, Her2 positive breast cancer, and triple negative breast cancer; endocrine cancer; soft tissue sarcoma such as fibrosarcoma, rhabdomyosarcoma, angiosarcoma, Kaposi sarcoma; Osteosarcoma, myeloma, osteosarcoma, Ewing tumor, fibrosarcoma, osteochondroma, osteoblastoma, and chondroblastoma; mesothelioma; skin cancer, basal cell carcinoma, squamous cell carcinoma, Merkel Cell carcinoma and melanoma; central nervous system Neoplasms of the brain, such as astrocytoma, glioblastoma, glioma, neuroblastoma, and retinoblastoma; lymphoma and leukemia, such as B-cell non-Hodgkin lymphoma (NHL), T-cell non-Hodgkin Lymphoma, chronic B-cell lymphocytic leukemia (B-CLL), chronic T-cell lymphocytic leukemia (T-CLL), Hodgkin's disease (HD), large granular lymphocytic leukemia (LGL), chronic myeloid leukemia (CML), Acute myeloid / myelocytic leukemia (AML), acute lymphoid / lymphoblastic leukemia (ALL), multiple myeloma (MM), plasmacytoma, and myelodysplastic syndrome (MDS). As would be appreciated by one of ordinary skill, PD1 and PD-L1 inhibitors are often accompanied by one or more additional cell checkpoint inhibitors. As such, additional embodiments of the invention can include administering one or more cell checkpoint inhibitors such as a cytotoxic T-lymphocyte associated protein 4 (CTLA-4) inhibitor, which can further be selected from: Ipilimumab, tremelimumab, a small-inhibitory RNA (siRNA), short hairpin RNA (shRNA), bifunctional RNA, antisense oligonucleotide, anti-CTLA-4 antibody or functional fragment thereof, a ribozyme, a deoxyribozyme, or an aptamer. In another embodiments of the invention can include administering one or more cell checkpoint inhibitors such as a lymphocyte-activation gene 3 (LAG-3) inhibitor, which can further be selected from: Relatlimab, a small-inhibitory RNA (siRNA), short hairpin RNA (shRNA), bifunctional RNA, antisense oligonucleotide, anti-LAG-3 antibody or functional fragment thereof, a ribozyme, a deoxyribozyme, or an aptamer. In another embodiment, the invention includes methods of treating cancer which can include the step of administering a therapeutically effective amount of a PD1 or PD-L1 inhibitor to a subject in need thereof. In this specific embodiment, the levels of Peroxiredoxin 6 (PRDX6) in the cancer cell of the subject are at a level, when compared to a reference level, indicative that the subject will respond to the administration of a therapeutically effective amount the a PD1 or PD-L1 inhibitor. In a preferred embodiment, the level of PRDX6 indicative that the subject will respond to the administration of a therapeutically effective amount the a PD1 or PD-L1 inhibitor is a level that is less than that found in a wild type cell. In additional embodiments, the level of PRDX6 indicative that the subject will respond to the administration of a therapeutically effective amount the a PD1 or PD-L1 inhibitor can be determined through analysis and sampling of PRDX6 levels in cancer cells that have, and have not responded to administration of a therapeutically effective amount the a PD1 or PD-L1 inhibitor. The invention includes methods of treating a subject having a cancer. In this embodiment, the method includes determining the level of PRDX6 in: i) a test sample obtained from the subject, and ii) a control sample. Next, the methods includes optionally obtaining a reference value corresponding to a level of PRDX6, wherein the level of PRDX6 in the test sample relative to the control sample or the reference value indicates whether the subject will respond to the administration of a therapeutically effective amount of at least one PD1 or PD-L1 inhibitor. In this embodiment, the reference value corresponds to the level of PRDX6 indictive that the subject will respond to the PD1 or PD-L1 inhibitor, or a level of PRDX6 indictive that the subject will not respond to the PD1 or PD-L1 inhibitor. Generally, a PDRX6 level being lower than a wild type level of expression of PDRX6 is indictive that the subject will respond to the PD1 or PD-L1 inhibitor, while a PDRX6 level being at or above a wild type level of expression of PDRX6 is indictive that the subject will not respond to the PD1 or PD-L1 inhibitor, and can further direct the administration of a PDRX6 inhibitor as described herein. Next, the methods includes identifying the subject as having a cancer involving a level of PRDX6 indictive that the subject will respond to the PD1 or PD-L1 inhibitor based on the level of PRDX6 in the test sample, and administering an effective amount of a PD1 or PD-L1 inhibitor to the subject to treat the cancer, the level preferably being lower than a wild type level of expression of PDRX6. As an alternative step, the method can include identifying the subject as having the cancer not involving a level of PRDX6 indictive that the subject will not respond to the PD1 or PD-L1 inhibitor based on the level of PRDX6 in the test sample, and withholding the administration of the PD1 or PD-L1 inhibitor to the subject, and optionally, administering a cancer therapy other than the PD1 or PD-L1 inhibitor to the subject to treat the cancer. In this embodiment, the levels of PRDX6 may be consistent or higher than wilt type levels, and may further include resistant to PRDX6 inhibitors as generally described herein. As described above, the control sample can be obtained from a) an individual belonging to the same species as the subject and not having cancer, or b) an individual belonging to the same species as the subject and known to have a cancer having a level of PRDX6 indictive that the subject will respond to the PD1 or PD-L1 inhibitor, or c) an individual belonging to the same species as the subject and known to have a cancer having a level of PRDX6 indictive that the subject will not respond to the PD1 or PD-L1 inhibitor. Notably, the control sample can be collected and tested prior to or concurrently with the specimen recovered from the subject. The method of determining the levels of PRDX6 levels in the control and subject sample includes measuring levels of PRDX6 RNA transcripts. In certain other embodiments, PRDX6 levels can be determined by Northern blot analysis, Western blot analysis, quantitative or semi- quantitative reverse transcription-polymerase chain reaction (RT-PCR), ligase chain reaction (LCR), transcription-mediated amplification (TMA), strand displacement amplification (SDA), and nucleic acid sequence-based amplification (NASBA). The method of assessing the efficacy or effectiveness of a PD1 or PD-L1 inhibitor therapy treatment being administered to a cancer subject. In a preferred embodiment, the method includes measuring the activity level of PRDX6 in a first sample obtained from the subject at a time t0. Next, the subject is administered a PD1 inhibitor and / or co-administered a PD1 inhibitor and a PRDX6 inhibitor, followed by measuring the activity level (which can include the activity of PDRX6, the activity of one or more of its domains, or the levels present in the second sample obtained from the subject at time t1. Here, a decrease in the level or activity (the term being interchangeable in this context) of biomarker PRDX6 in the second sample relative to the first sample is an indication that the PD1 treatment is or will be effective for treating cancer in the subject. Further, in another embodiment, a decrease in the level or activity of biomarker PRDX6 in response to a PRDX6 inhibitor in the second sample relative to the first sample is an indication that a PD-L1 treatment will be effective for treating cancer in the subject. The terminology used herein is for describing particular embodiments and is not intended to be limiting. As used herein, the singular forms “a,” “and” and “the” include plural referents unless the content and context clearly dictate otherwise. Thus, for example, a reference to “a” or “the” marker may include a combination of two or more such markers. Unless defined otherwise, all scientific and technical terms are to be understood as having the same meaning as commonly used in the art to which they pertain. For the purposes of the present invention, the following terms are defined below. The terms “comprises”, “comprising”, are intended to have the broad meaning ascribed to them in U.S. Patent Law and can mean “includes”, “including” and the like. The invention now being generally described will be more readily understood by reference to the following examples, which are included merely for the purposes of illustration of certain embodiments of the embodiments of the present invention. The examples are not intended to limit the invention, as one of skill in the art would recognize from the above teachings and the following examples that other techniques and methods can satisfy the claims and can be employed without departing from the scope of the claimed invention. Indeed, while this invention has been particularly shown and described with references to preferred embodiments thereof, it will be understood by those skilled in the art that various changes in form and details may be made therein without departing from the scope of the invention encompassed by the appended claims. EXAMPLES Example 1: Rationale for use of PRDX6 as a Predictive Biomarker and Therapeutic Cancer Target. Currently there is little or no knowledge about biomarkers that are associated with HDAC inhibitor sensitivity in cancers. As demonstrated in Figures 1-7, these data demonstrate that PRDX6 can act as a predictive biomarker for cancer, and in particular a predictive biomarker for the therapeutic application of HDAC inhibitors. As described above, PRDX6 ‘s use as a biomarker cannot only be used to predict patient responses to novel HDAC inhibitors, but can also be a therapeutic target for treating cancer. It has been known for years that DMSO and butyrate, two known relatively nonspecific inhibitors of HDACs, can induce certain leukemia cells to differentiate and suppress neoplastic growth 6. In recent years, HDACs become widely recognized as key players in epigenetic regulation by modulating chromatin opening and transcription 2. Consequently, inhibitors of HDAC enzymes (HDACi) have been developed as anti-cancer drugs. There are 18 HDAC enzymes in the human genome that can be classified into four classes 7. There are four FDA approved HDAC inhibitors. Pan-HDAC inhibitors (SAHA, Panobinostat and Belinostat) are hydroxamates. Romidepsin is a natural product depsipeptide that is class I selective 7. However, the approved HDAC inhibitors still have significant limitations in pharmacokinetic drawbacks, oral bioavailability, dose limiting toxicity and thereby limiting their use for drug combination therapies. In 2009, Applicant’s discovered a new analog of natural product Largazole exhibits broad anti-tumor activities, referred to herein as Paragazole / OKI-5. Applicants demonstrated that Paragazole suppresses tumor formation in a dose-dependent manner. Phase I results showed that the pro-drug form of Paragazole / OKI-5, referred to as OKI-179 is well tolerated with high targeting activity. Since acquired drug resistance is associated with many, if not all, anticancer therapeutics, Applicants sought to understand the potential mechanism(s) for developing reduced sensitivity to drugs like OKI-179. Towards this goal, Applicants developed a genome-wide CRISPRa screen that aimed to identify genes whose overexpression leads to resistance to Largazole or Paragazole in HCT116 colon cancer cells. After two-round of drug challenges by Largazole exposure, Applicants uncovered a subset of genes that were highly enriched (Fig.1-C). On top of this list is ASS1, a gene that has been shown to modulate HDAC inhibitor sensitivity recently. This result suggests that the screen can recover a hit that has been validated in the literature. Applicants subsequently tested hits on the top-ten list individually and found that overexpression of PRDX6 renders HCT116 resistance to Largazole treatment (Fig. 3). Peroxiredoxin 6 (PRDX6) (PRDX6 nucleotide sequence according to SEQ ID NO. 1; PRDX6 amino acid sequence according to SEQ ID NO. 2) is a bifunctional enzyme with glutathione peroxidase activity (GPx) and Ca2+-independent phospholipase A2 (iPLA2) activity. Higher expression of PRDX6 has been observed in various cancer cells and elevated PRDX6 could facilitate resistance to radiation and chemotherapeutics. Depletion of PRDX6 with shRNA makes HCT116 more sensitive to Largazole treatment and such effect can be rescued by ectopically expressing an shRNA resistant PRDX6 variant. Dose-responsive analysis of HCT116 cells with or without PRDX6 to Paragazole treatment shows that there is at least 5 fold reduction in IC50 upon PRDX6 knockdown, suggesting PRDX6 modulates Largazole or Paragazole growth inhibitory responses. These results suggest that PRDX6 expression is associated with the development of Largazole / Paragazole resistance and could be a predictive biomarker for patient stratification. Moreover, direct inhibition of PRDX6 can also be included as a treatment for cancer. Example 2: Genome-wide CRISPR-HTP screen for largazole Given largazole's potent antiproliferative effects on colon cancer cells, our aim was to identify any gene that, when overexpressed, could alter the sensitivity of these cells to largazole treatment. To do this, Applicants first created a HCT116 cell line that permanently expresses CRISPR-dCas9-VP64. Applicants then transduced this cell line with a lentivirus containing a total of 104,540 sgRNAs, equating to 5 sgRNAs per gene, at a multiplicity of infection (MOI) of less than 0.5. This ensured a low likelihood of multiple transductions for each cell, thus avoiding the potential for unnecessary multiple overexpression. Having created the CRISPRa cell library, Applicants split the cells into two groups: one half was treated with DMSO, and the other half was treated with 100 nM of largazole. Applicants then isolated genomic DNA and enriched, amplified, and processed the sgRNA-encoding region for sequencing (Figure 2.1). Upon sequencing, Applicants analyzed the data by comparing the enrichment of the largazole-treated sample against the DMSO-treated sample using PinAPL-Py. For each sample, genes with fewer than 2 sgRNAs were filtered out as nonspecific, and Applicants ranked the total count for each sgRNA under their corresponding gene's name (Figure 2.2A). To add another layer to the analysis, Applicants summed up all readings of sgRNAs for each gene and calculated the fold change for each gene by comparing the largazole-treated group with the DMSO-treated group. Applicants also used the p-value as another parameter to validate the results. With a cutoff set at p-value < 2*10^7, Applicants identified 202 significant genes that were enriched upon largazole treatment (Figure 2.2B). Notably, ASS1 was at the top of our enrichment list, confirming the success of the screen, as it has been previously reported that ASS1 knockdown showed sensitization to other HDACi treatments. To gain a better understanding of the signaling pathways involved with largazole, Applicants further analyzed the enrichment results using Gene Ontology (GO) enrichment analysis. Applicants looked at both molecular functions and biological processes and found that transcription factor activity was highly involved. Furthermore, the regulation of transcription from RNA polymerase II (RNA Pol II) promoter regions was affected, which in turn affected overall autophagy (Figure 2.3). Example 3: Secondary screen and individual verification for primary screen. In order to validate the results from the primary screen, it's customary to conduct a secondary, more focused screen. This typically involves ordering a custom sgRNA pool comprising the top 500 genes on the list and performing the screen again with this focused sgRNA pool. In our case, however, Applicants took a different approach: Applicants retrieved our sequencing samples from the primary screen and recloned the fragments back into the original vector to create our own focused library. This strategy enabled us to further amplify the truly enriched genes while diminishing or reducing the amplification of any false-positive signals. This approach not only saved us time that would have been spent waiting for a custom pool, but it was also more cost-effective than ordering an oligo pool. After conducting the secondary screen, Applicants ranked each sgRNA by their total counts, as Applicants did for the primary screen. ASS1 was further amplified and topped the list, confirming the validity of our unique strategy (Figure 2.4). Following the secondary screen, Applicants decided to individually test the top 10 genes. To do this, Applicants transduced wild-type HCT116 cells with recombinant DNA plasmids expressing each target gene that Applicants were able to acquire. Each cell line was then treated with 100 nM of largazole, as Applicants had done for the screen, along with wild-type cells. This was to assess whether overexpressing each gene would result in desensitization. As a result, three of the cell lines showed increased tolerance to largazole compared to the wild-type cells, while two others showed increased sensitivity to largazole when overexpressed (Figure 2.5A and B). The sensitization observed in the two cell lines could potentially be due to off-target effects and warrants further investigation. These results further underline the importance of orthogonal validation. Example 4: PRDX6 alters cells’ sensitivity to largazole in HDAC-independent manner. Once the targets were verified, Applicants chose to focus on PRDX6 for our mechanistic studies due to considerations of workload, with ASS1 serving as our control. Our first step was to determine whether cells overexpressing either ASS1 or PRDX6 would affect the response of HDAC to largazole treatment. Applicants treated both ASS1 overexpressing HCT116 cells (HCT116 ASS1 OE) and PRDX6 overexpressing HCT116 cells (HCT116 PRDX6 OE) with varying concentrations of largazole. A western blot was then performed to observe whether the response of acetylation would be changed by overexpression. Both cell lines showed similar results to wild-type cells, indicating that the tolerance induced by overexpression is independent of largazole's HDAC inhibitory effect (Figure 2.6). Given that PRDX6 has two major functions - glutathione peroxidase (GPx) and phospholipase A2 (PLA2), Applicants were curious to know whether these functions were connected to largazole desensitization. To investigate this, Applicants generated PRDX6 knockdown (PRDX6 KD) cells, KD cells with wild-type rescue, KD cells with a GPx function mutation (S32A), KD cells with a PLA2 function mutation (C47S), and KD cells with both functions mutated, all from HCT116 wild-type cells (Figure 2.7A). As with the previously reported sensitization of HDACi by ASS1 knockdown, PRDX6 KD sensitized HCT116 cells to largazole treatment. This sensitization could be rescued with overexpression of either WT, S32A, or C47S PRDX6, while double knockdown showed the same level of sensitization as PRDX6 KD cells (Figure 2.7B and C). This suggests that both of PRDX6’s functions are involved in largazole sensitization, although further western blotting showed that neither function is related to HDAC (Figure 2.7D). To confirm our hypothesis that PRDX6 induced sensitization of largazole is PRDX6 function-related, Applicants treated HCT116 wild-type cells with MJ33, a selective reversible inhibitor of PRDX6 PLA2 function. Applicants used a 9 + 3 treatment: first, cells were treated with 100 nM of largazole for 9 days, then one third of them were continuously treated with 100 nM of largazole, one third were treated with 10 μM of MJ33, and the last third were treated with largazole + MJ33 for another 3 days (Figure 2.8A). By using MJ33, Applicants mimicked the PRDX6 KD C47S cell line. The results showed a difference between largazole treated and largazole + MJ33 treated cells (Figure 2.8B and C). MJ33 itself displayed no antiproliferative activity on HCT116 cells (Figure 2.8D and E). This further affirmed our conclusion that PRDX6 induced sensitization of largazole is PRDX6 function dependent. Example 5: ATAC-seq reveals increased chromatin accessibility at promoter regions with largazole treatment in PRDX6 knockdown cells. Following the discovery that PRDX6 knockdown induced sensitization of largazole is independent of HDAC, Applicants employed ATAC-seq to investigate any genomic differences between wild-type and knockdown cells post-treatment. Given that largazole is an HDAC inhibitor, it was expected that chromatin accessibility would increase after treatment (Figure 3.1A). Previous research has reported that largazole treatment suppresses super enhancers. Consistent with these findings, Applicants observed a significant decrease in accessibility in promoter regions when Applicants compared our ATAC-seq data with ChIP-seq data from other groups' databases (Figure 3.1B). Intriguingly, PRDX6 knockdown cells treated with largazole showed a substantial increase in chromatin accessibility, including regions that were closed in wild-type cells (Figure 3.1C and D). Upon noticing the differences in promoter regions between wild-type and knockdown cells, Applicants hypothesized that certain transcription factors (TFs) may be repressed in wild-type cells but activated in knockdown cells. To test this, Applicants conducted a Transcription Factor Enrichment Analysis (TFEA) of our ATAC-seq data to identify any differences in TFs between wild-type and knockdown cells. As expected, Applicants found that SP1 was the TF with the largest discrepancy compared to other TFs, including YY1 (Figure 3.2A-D). Given these results, Applicants decided to focus our attention on SP1 and perform a ChIP-seq to gain further insights into these differences. Example 6: SP1 ChIP-seq reveals mechanistic action of PRDX6 induced sensitization of largazole. Upon observing increased accessibility in SP1 regions in PRDX6 knockdown cells treated with largazole, Applicants proceeded with SP1 ChIP-seq for both wild-type and knockdown cell lines, with and without largazole treatment. Our SP1 ChIP-seq data revealed that SP1 was repressed after treatment in both cell lines, with even greater repression in the knockdown cell line, a finding that contrasted with our ATAC-seq results (Figure 3.3A and B). To reconcile the differences between ATAC-seq and SP1 ChIP-seq data, Applicants hypothesized that largazole treatment represses SP1 in both cell lines, while other transcription factors (TFs) in the knockdown cell line replace SP1, maintaining accessibility in those regions. Applicants tested this hypothesis by conducting a Transcription Factor Enrichment Analysis (TFEA) of our SP1 ChIP-seq data to identify other possible TFs at repressed SP1 regions. As Applicants expected, Applicants found KLF3 was highly enriched in knockdown cells compared to wild-type cells (Figure 3.3 C and D). Considering that KLF3 has been reported by other groups as a transcription repressor, it is reasonable to propose that the mechanistic action of PRDX6 induced sensitization of largazole is due to PRDX6 knockdown increasing the degradation rate of SP1 upon largazole treatment, which in turn increases KLF3 replacement and further induces genome-wide repression at all SP1 binding regions. It's worth noting that the TFEA result for KLF3 is biased because the binding motifs of KLFs are very similar and hard to distinguish. Therefore, to validate our interpretation of the TFEA and our hypothesis, Applicants performed a western blot for both SP1 and KLFs including KLF3, 4, 15. As expected, Applicants found that SP1 degradation is faster for PRDX6 knockdown cells with largazole treatment and the dynamic of KLFs is different than SP1 (Figure 3.4A and B). This result suggests that KLFs have the opportunity to replace SP1. However, it remains unknown which KLF is dominant in the replacement process, and further investigation is needed. Example 7: scRNA-seq reveals KLF2 as an important factor of adaptive resistance of largazole Having studied the mechanism of action, Applicants next turned our attention to long-term resistant cells. Adaptive resistance was consistently observed when Applicants treated wild-type HCT116 cells with largazole. To investigate this, Applicants cultured wild-type HCT116 cells with 100 nM largazole for 15 days, and resistant cells were submitted for scRNA-seq analysis alongside the same batch of naive cells that were stored in liquid nitrogen when the treatment started. Remarkably, the two groups of cells were similar, with only five out of 16 clusters showing more than 100 genes upregulated by more than 0.25-fold (Figure 3.5A and B). Contrary to our expectations, no upregulation of PRDX6 was observed, possibly due to the reading depth of scRNA-seq, which is one of the limitations of this technique. Instead of PRDX6, Applicants found multiple KLFs being upregulated in various clusters. This suggests that KLFs may be involved in adaptive resistance (Table 1.3A). Moreover, KLF2 was upregulated in almost every cluster upon conducting a differential expression analysis, indicating that KLF2 is the major KLF responsible for adaptive resistance of largazole (Table 1.3B). Example 8: SP1 is post-translationally modified by largazole. Observing a faster degradation of SP1 in PRDX6 knockdown cells treated with largazole, the primary question Applicants sought to answer was whether this was due to transcriptional or post-translational effects. To this end, Applicants performed real-time quantitative polymerase chain reaction (RT-qPCR) on both wild-type and PRDX6 knockdown HCT116 cells treated with largazole in a time-dependent manner. The results showed that both SP1 and PRDX6 mRNA levels decreased upon treatment, providing a possible explanation for the absence of PRDX6 enrichment in our scRNA-seq dataset (Figure 4.1). Moreover, real-time PCR validated a satisfactory PRDX6 knockdown in the cells. Having confirmed that the accelerated degradation of SP1 was not transcriptional, Applicants sought to ascertain if it was post-translational. To this end, Applicants performed microscale thermophoresis with His-tagged SP1 and paragazole thiol, an active analog of largazole thiol designed for targeting class 1 HDACs without inhibiting class IIa HDACs (Figure 4.2). As anticipated, the results showed a separation between the SP1 + DMSO mixture and the SP1 + paragazole thiol mixture, indicating a binding event between SP1 and paragazole thiol (Figure 4.3A). Given that PRDX knockdown in cells generally induces increased oxidative stress, Applicants added hydrogen peroxide to both mixtures to investigate whether the interaction between SP1 and pargazole thiol could be heightened in an oxidative environment. As demonstrated, under oxidative conditions, the separation between the two mixtures increased, indicating a stronger binding between SP1 and paragazole thiol (Figure 4.3B). Furthermore, due to the thiol functional group in pargazole thiol, which would form a disulfide bond with serine residues of SP1 under oxidative stress, Applicants sought to confirm if the interaction was indeed a disulfide bond. Applicants added 5 mM DTT to both mixtures and observed no separation between the two, indicating that the interaction between SP1 and paragazole thiol was indeed a disulfide bond and could be reinforced under oxidative stress (Figure 4.3C). After establishing the direct interaction between SP1 and paragazole thiol, Applicants wanted to discern if this interaction would interfere with the binding between SP1 and DNA. This is due to reports that modulations of SP1 induce SP1 DNA disassociation, which could cause the faster degradation of SP1 Applicants observed. Applicants designed an oligo matching the binding motif of SP1 and used it in a thermophoresis experiment with SP1 as Applicants did with paragazole thiol. As expected, separation was observed, indicating a binding event between SP1 and the oligo (Figure 4.4A). Applicants then added the same quantity of paragazole thiol to both samples to test whether its binding would interfere with the interaction between SP1 and the oligo. As shown, adding paragazole thiol had no effect on the DNA-binding ability of SP1 (Figure 4.4B). Lastly, Applicants used SP1 + paragazole + hydrogen peroxide to test whether a reinforced interaction of SP1 and paragazole thiol would interfere with SP1-oligo interaction. However, the results remained the same (Figure 4.4C). This suggests that while the interaction between SP1 and paragazole thiol does not interfere with the association between SP1 and DNA, oxidative stress- induced reinforcement of the interaction between SP1 and paragazole thiol could expedite the degradation of SP1. This finding provides some explanation of the mechanism underlying the PRDX6 knockdown-induced sensitization to largazole treatment. However, further investigations are necessary to provide a more detailed elucidation of this mechanism. Example 9. PRDX6 is post-translationally modified by largazole. Upon finding a direct interaction between SP1 and paragazole thiol, Applicants sought to determine if PRDX6 exhibited a similar interaction with paragazole thiol. Notably, PRDX6 has a single serine residue, which is responsible for the GPx activity of PRDX6. Applicants found that when PRDX6 was mixed with paragazole thiol under normal conditions, no interaction was observed between them (Figure 4.5A). However, when these two components were mixed in an oxidative environment, a strong interaction was demonstrated, suggesting a binding event between PRDX6 and paragazole thiol (Figure 4.5B). Further, when Applicants added 5 mM DTT to each sample, the separation disappeared, indicating that the interaction between PRDX6 and paragazole thiol is a disulfide bond, similar to the interaction between SP1 and paragazole thiol (Figure 4.5C). Similar to our approach with SP1, Applicants wanted to explore if this interaction would interfere with the function of PRDX6 as a GPx. Therefore, Applicants developed a PRDX6 GPx function assay by adapting a current method to suit our needs. Briefly, purified PRDX6 protein was mixed with hydrogen peroxide in phosphate buffer and incubated at room temperature in the dark for 30 minutes. After incubation, samples were mixed with HRP buffer and 3,5-dichloro-2- hydroxybenzenesulfonic acid (DHBS) for another 30 minutes under the same conditions. The mixtures were then tested for absorbance at 520 nm. Using this method, Applicants measured the activity of our PRDX6 to be approximately 100 pmole / ug / min (Figure 4.6A). Contrary to our expectations of inhibition, Applicants observed enhanced hydrogen peroxide consumption when paragazole thiol was mixed with PRDX6 (Figure 4.5B and C). This was logical, as the conjugation of PRDX6 and paragazole thiol initiated with the consumption of hydrogen peroxide. Therefore, the increased consumption of peroxide was evidence of the conjugation of PRDX6 and paragazole thiol taking place (Figure 4.5D). After confirming the conjugation and its reaction mechanism, Applicants sought to provide additional supporting evidence, including in vivo data. Thus, Applicants ran two samples, PRDX6 + DMSO + hydrogen peroxide and PRDX6 + paragazole thiol + hydrogen peroxide, through intact mass spectrometry. Applicants observed a notable peak shift in the conjugated sample, with the size of the shift being exactly 480.5 Dalton, the exact mass of conjugated paragazole thiol (Figure 4.7A). This represented the most solid evidence of conjugation, negating the need for further in vitro studies. Applicants subsequently shifted our focus to in vivo experiments. Applicants performed a cellular thermal shift assay (CESTA), which can serve as evidence of direct conjugation between PRDX6 and paragazole, using MJ33 as our positive control (Figure 4.7B). Both MJ33 and paragazole showed stronger thermal stability with slightly increased stability for largazole compared to DMSO at 56 °C. This further supported our conclusion, even in vivo, and finalized our study on the interaction between PRDX6 and paragazole. Despite having accumulated a significant amount of data, there are still gaps in our understanding of the mechanism of action. For instance, direct evidence of SP1 paragazole thiol conjugation to show that conjugated SP1 degrades faster than normal SP1 is lacking. More studies are needed to fill these gaps and further our understanding of this process. Our team will continue to pursue these lines of investigation in the future. Example 10. Cell type specificity study of PRDX6 induced sensitization of largazole Our experiments have thus far utilized HCT116 cells, leading us to question whether the mechanism of action we've discovered is specific to this cell line or if it can be extrapolated to other cell lines. To answer this, Applicants developed PRDX6 knockdowns in five other distinct cell lines: MDA-MB-231, MDA-MB-468, A223, TCh3, and TAb2. Applicants included two human breast cancer cell lines in this study, given reports of largazole exhibiting potent antiproliferative activity against breast cancers. The remaining three lines are mouse squamous carcinoma cell lines, chosen to investigate whether the mechanism is human-specific. Our results revealed a cell type specificity across cell lines, with MDA-MB-468 demonstrating the most significant IC50 separation among the lines tested. In contrast, TAb2 showed no discernable difference between wild-type cells and PRDX6 knockdown cells (Figure 5.1 A-F). A slight difference was detectable in MDA-MB-231, A223, and TCh3 cell lines after analysis, suggesting that an alternative regulatory mechanism may be at play within these cell lines (Table 5.1). These findings indicate the need for further studies to understand the discrepancies across cell lines better and to shed more light on the mechanism Applicants have uncovered. Example 11. Drug specificity study of PRDX6 induced sensitization of largazole. Having explored cell type specificity, Applicants then sought to determine if the mechanism is specific to largazole and paragazole only. Applicants treated HCT116 wild-type and PRDX6 knockdown cells with various HDAC inhibitors (HDACis) to see if Applicants could observe any sensitization with other drugs. Applicants selected belinostat (PXD101), entinostat (MS-275), vorinostat (SAHA), romidepcin (FK228), and panominostat (LBH589) for our experiment. Entinostat and romidepcin were particularly interesting to us because entinostat is a class I HDACi like largazole and paragazole, and romidepcin is categorized as a depsipeptide like largazole and paragazole. A Our results showed that, except for entinostat, none of the other drugs displayed increased sensitivity in PRDX6 knockdown cells, and even the sensitization with entinostat was mild (Figure 5.2A-F) (Table 5.2). This makes sense given that the mechanism of action of PRDX6-induced sensitization of largazole / paragazole is driven by their direct interaction with both SP1 and PRDX6. The observed sensitization with entinostat warrants further investigation for a clearer understanding. During the HDACi tests, Applicants observed that paragazole demonstrated greater separation than largazole, prompting us to explore the reason for this. Initially, Applicants performed RT-qPCR for cells treated with either largazole or paragazole at their respective IC50 concentrations for 48 hours, similar to what Applicants did for SP1 and PRDX6. The results showed no difference in mRNA levels between largazole and paragazole treatments, indicating that the observed difference should be post-translational (Figure 5.3A). To investigate this further, Applicants treated cells with all the tested HDACis at their IC50 concentrations for 48 hours and used western blotting to determine the protein level of PRDX6 in each sample. Interestingly, all treatments resulted in decreased PRDX6 protein levels, with paragazole showing the most significant reduction. This suggests that the difference Applicants observed in the IC50 test is post- translational and that more detailed investigation is needed for a better understanding (Figure 5.3B). Example 12. TCGA analysis reveals PRDX6 as a potential biomarker of cancer aggressiveness. Having observed delayed proliferative activity in the xenograft model, and consistent similar phenotypes in previous cell studies, Applicants began to investigate whether the expression level of PRDX6 could serve as a significant predictor of cancer aggressiveness in patients. To this end, Applicants utilized the TCGA database to identify any cancer types associated with significantly higher levels of PRDX6 expression. Encouragingly, Applicants found that overall cancer aggressiveness slightly increases with high expression of PRDX6, and seven types of cancer exhibited significantly upregulated PRDX6. These include head and neck squamous cell carcinoma (HNSCC), adrenocortical carcinoma (ACC), breast invasive carcinoma (BRCA), kidney renal papillary cell carcinoma (KIRP), brain lower grade glioma (LGG), lung adenocarcinoma (LUAD), and uterine corpus endometrial carcinoma (UCEC) (Figure 6.3 A-I). For a more precise exploration of this concept, Applicants also searched the TCGA database for every recorded PRDX6 expression level, filtering for data that included PRDX6 expression levels in both normal tissue and tumor tissue, and then examined the overall survival for these patients. As anticipated, Applicants found a larger separation of overall survival than Applicants had previously observed, further supporting our hypothesis that PRDX6 serves as a biomarker for predicting cancer aggressiveness (Figure 6.2). Following the investigation into the TCGA database, Applicants aimed to test whether our hypothesis held true at the cellular level. To accomplish this, Applicants chose HNSC as our study target, as it exhibited the most significant separation among the cancer types examined. Applicants then compared the natural proliferation rate between wild-type cells and PRDX6 knockdown cells using three derived cell lines of squamous carcinoma: A233, TCh3, and TAb2. As our results demonstrated, all three cell lines exhibited delayed proliferation with PRDX6 knockdown, reinforcing the notion that PRDX6 serves as a biomarker of cancer aggressiveness (Figure 6.3A- C). Example 13. Materials and Methods (Figure Series 2). DNA transfection and virus infection: Lentivirus was produced by transfecting HEK293T cells with standard packaging vectors using 1mg / mL PEI (Polysciences, Inc., 1:5 μg DNA: μg PEI). Cultural medium was replaced 8 hours after transfection, and supernatant was harvested 2 days after medium replacement. Lentivirus supernatant was further filtered by 0.2 μm PVDF filters (Thermo Scientific™ Nalgene™) and mixed with polybrene (Sigma-Aldrich®, 10 μg / mL) before infection. Generation of cell lines To generate HCT116 cell line stably expressing dCas9-VP64- GFP, WT HCT116 cells (ATCC) were transduced with lentiviral vector expressing dCas9-VP64- GFP from an EF1A promoter (Addgene, #61422) and selected for GFP-positive cells using two rounds of fluorescence activated cell sorting (FACS) on BD FACSAria Fusion. To generate HCT116 cell lines stably expressing ASS1, PCED1B, R3HDM2, ENO2 and PRDX6, WT HCT116 cells (ATCC) were transduced with lentiviral PXL304 vector expressing indicated gene from an CMV promoter with a C-terminal V5 tag (ccsbBroad304, #00116, #04547, #15744, #08626, #06161, #02204) and selected for blasticidin-positive cells using blasticidin (Gibco™, 10 μg / mL). To generate HCT116 PRDX6 KD, WT HCT116 (ATCC) cells were transduced with lentiviral pLOK.1 vector expressing shRNA from an U6 promoter (TRC#N0000052157) and selected for puromycin-positive cells using puromycin (TOCRIS®, 2 μg / mL). To generate HCT116 PRDX6 KD with PRDX6 WT, PRDX6 S32A, PRDX6 C47S and PRDX6 S32A C47S rescue cell lines, HCT116 PRDX6 KD cells were transduced with 100x library coverage genome-scale CRISPRa screening: Genome-scale screen was conducted similar to the construction described by Weissman Lab (https: / / weissman.wi.mit.edu / crispr / ). The CRISPRa v2 library (Addgene, #83978) were transduced into HCT116 CRISPRa cells, at MOI < 0.5 (percentage of transduced cells 2 days after transduction: 40-50%, checked by BFP fluorescence ratio using BD FACSCelesta). 2 days after transduction, cells were selected with 2 μg / mL puromycin for 2 days to reach the point which transduced cells accounted for 95-99% of the population. After the selection, 100x library coverage (25-30*106 cells) were harvested and the remaining cells were split into two populations for untreated and largazole-treated growth. Two populations were cultured in 15 cm culture dishes with seeding density 5*106 for each dish at the beginning. Untreated and largazole-treated population were harvested after each dish reached cell density at 20*106 (largazole-treated population was treated by 100 nM largazole, additional pulses of largazole treatment were performed every 3 days). Genomic DNA was isolated from frozen cell pellets and sgRNA- encoding region was enriched, amplified, and processed for sequencing on Illumina NovaSeq6000. Sequenced libraries were analyzed using PinAPL-Py (www.pinapl-py.ucsd.edu) (Sci Rep. 2017 Nov 20;7(1):15854.). The project parameters were defined in the following way: the screen type was set as “enrichment”, the 5’-adapter sequence, and the reference library was obtained from the Weissman Lab repository at Addgene (https: / / www.addgene.org / pooled-library / weissman- human-crispra-v2 / ). Applicants used the sgRNA ranking files and removed all data points where the treated and control output contained zero counts and used R version 4.1.0 to generate the plots. Focused CRISPRa library generation and screening: Oligonucleotide pool were retrieved from 100x genome-scale screening sequence sample and cloned into the sgRNA expression vector pCRISPRia-v2 (Addgene, #84832). Focused library screen and analysis were conducted in the same manner as described previously. Cell viability assay and individual validation of potential genes: 3*105cells were seeded into each well of 6-well plate. After 24 hours of incubation, DMEM were replaced by fresh DMEM with 100 nM largazole. Additional pulses of largazole treatment were performed every 3 days. After total 12 days treatment, cells were washed by D-PBS twice and incubated with 1 mL of 4% formaldehyde in D-PBS under room temperature, 100 RPM shaking for 10 minutes (Thermo, MaxQ 2000). Cells were washed again with D-PBS after incubation and incubated with 1 mL of 0.05% crystal violet staining buffer (250 mL MeOH, 750 mL MiliQ water, 0.5g crystal violet) under room temperature, 100 RPM shaking for 10 minutes. Cells were washed with DI water and air dried for 24 hours. Dried stained samples were captured by camera (Nikon D5600, by the courtesy of Hongxuan Chen) and resolubilized using 6 mL of solubilization buffer (400 mL EtOH, 100 mL MeOH, 100 mL MiliQ water) under 4°C, 100 RPM shaking for 1 hour. Resolubilized samples were further quantified by plate reader (absorbance 530 nm, Molecular Devices SpectraMAX iD3). Individual validation of potential genes was performed by seeding 3*105 of each cell line into 6-well plate in duplicate, followed with cell viability assay procedure. Immunoblotting analysis: Cells with different treatments were harvested and lysed in RIPA buffer. Cell lysates were separated on SDS-PAGE gels and transferred to nitrocellulose membranes (Amersham™ Protran™, 0.2 μm). After blocking nonspecific bindings with blocking buffer (5% non-fat milk in TBST) for 45 minutes at room temperature, membranes were immunoblotted with primary antibodies 1.5 hours at room temperature. After, membranes were incubated with HRP-conjugated donkey anti-rabbit / sheep anti-mouse secondary antibody for 1 hour at room temperature. The protein bands were developed with SuperSingal™ west dura extended duration substrate (Thermo, lot#X8340749) and detected by ImageQuant™ LAS 4000 (GE healthcare) Largazole and MJ33 combination assay: 3*105of HCT116 wild-type cells were seeded into each well of 6-well plates. After 24 hours of incubation, DMEM was replaced by fresh DMEM with 100 nM largazole. More additional pulse of largazole treatment were performed each 3 days. Cells were washed twice by D-PBS after total 9 days treatment, and each well was treated either with 2 mL of 100 nM largazole, 10 μM MJ33 or 100 nM largazole + 10 μM MJ33 for 3 days. Cells were conducted and quantified as cell viability assay after 3 days treatment. Statistical analysis: Statistical significance was determined by Microsoft® Excel®. Data are represented as mean ± SD. Student’s t-test was used for statistical analysis for data and p-value < 0.05 was considered as statistically significant. Example 14. Materials and Methods (Figure Series 3). Spike-in ATAC-seq: Cryopreserved nuclei were sent to Active Motif to perform the ATAC-seq assay. The nuclei were then thawed in a 37 o C water bath, pelleted, washed with cold PBS.200k HTC166 nuclei were mixed with 40k drosophila S2 nuclei for each ATAC reaction and biological duplicates were included for the experiments. ATAC-seq experiments were carried out as previously described, with some modifications based on. Briefly, nuclei (containing spike-in S2 nuclei) were resuspended in lysis buffer, pelleted, and tagmented using the pre-loaded Tn5 transposase at 37°C for 30min. Tagmented DNA was then purified using the MinElute PCR purification kit (Qiagen), amplified with 11 cycles of PCR, and purified using Agencourt AMPure SPRI beads (Beckman Coulter). Resulting libraries were quantified using the KAPA Library Quantification Kit for Illumina platforms (KAPA Biosystems) and sequenced with PE42 sequencing on the NovaSeq 6000 sequencer (Illumina). Analysis of ATAC-seq data was very similar to the analysis of ChIP-Seq data. Reads were aligned consecutively to the human genome (hg38) and to the Drosophila genome (dm3) using the BWA algorithm (mem mode; default settings). Duplicate reads were removed, only reads mapping as matched pairs and only uniquely mapped reads (mapping quality >= 1) were used for further analysis. The number of human alignments used in the analysis was adjusted according to the number of Drosophila alignments that were counted in the samples that were compared. Alignments were extended in silico at their 3’-ends to a length of 200 bp and assigned to 32-nt bins along the genome. The resulting histograms (genomic “signal maps”) were stored in bigwig files. Peaks were identified using the MACS 2.1.0 algorithm at a cutoff of p-value 1e-7, without control file, and with the –nomodel option. Peaks that were on the ENCODE blacklist of known false ChIP-Seq peaks were removed. Signal maps and peak locations were used as input data to Active Motifs proprietary analysis program, which creates Excel tables containing detailed information on sample comparison, peak metrics, peak locations and gene annotations. Chromatin immunoprecipitation and ChIP-seq analysis: HCT116 WT and PRDX6 KD cells were treated with 100 nM largazole or DMSO for 12 hours and cross-linked with 1%formaldehyde for 15 minutes at room temperature (25◦C). Cells were washed two times with PBSand membranes ruptured in hypotonic buffer (50 mM NaCl, 1% NP-40 alternative, 2 mM EDTA, 10 mM Tris, 1 mM DTT, 2 mM EDTA, 1X protease inhibitor cocktail (Roche # 04693124001). The cell nuclei were recovered by centrifugation and resuspended in lysate buffer (150 mM NaCl, 0.5% Triton X-100, 2 mM EDTA, 0.1% SDS, 20 mM Tris, 1 mM DTT, 1X protease inhibitor cocktail). Resuspended samples were sonicated for 40 cycles (30 s ‘on’ at high level and 30s ‘off’ per cycle) using a Bioruptor (Diagenode; Denville, NJ, USA) and spun for 10 min at 16,000 g in a microcentrifuge. Samples were incubated for 3 hours at 4 °C with 5–20 μg of antibodies and 20 μL of 50% slurry with protein A beads (Millipore; Billerica, MA, USA). The immunoprecipitated chromatin was then recovered and DNA purified using phenol chloroform extraction. Sequencing libraries were prepared using an Illumina ChIP-Seq DNA Sample Prep Kit (cat. # IP-102-1001), with a starting sample varying from 2 to 20 ng of DNA isolated from the immunoprecipitation step. Antibodies used are as follows: SP1 (Santa Cruz sc-420x). ChIP-seq datasets were aligned using Bowtie mapping software version 0.12.7 (19). To maintain the same read length across all experiments, 1 × 150 bp ChIP-seq raw datasets (fastq files) were trimmed to 50 bp using FASTX-toolkit (version 0.0.13.2) (http: / / hannonlab.cshl.edu / fastx_toolkit / ) or Trimmomatic (version 0.36) (20). All reads were mapped to the hg18 reference human genome with a number of base pairs mismatch not >2 (96% sequence match). Applicants used SAMtools version 0.1.19 (21) to generate a sorted pileup format of the aligned reads. Reads were then extended from the 3′–end to a final length of 150 bp. For each experiment, genome coverage bed graph files were generated using BEDTools2 version 2.25.0 (22) and then normalized by multiplying the read density times 100 and dividing by the total number of mapped reads. Normalized bed graph files were subsequently converted to bigwig files and uploaded to UCSC Genome Browser for visualization. Fixed Single Cell RNA-seq and data analysis: Cells exhibiting >80% viability are fixed in a 4% formaldehyde fixative solution and using Chromium Next GEM Single Cell Fixed RNA Sample Preparation Kit (10x Genomics). The whole transcriptome probe pairs (10X Genomics) are added to the fixed single cell suspensions to hybridize to their complementary target RNA in an overnight incubation. After hybridization, the unbound probes are washed off. The fixed and probe-hybridized single cell suspensions are loaded onto Chromium X (10X Genomics) microfluidics instrument to generate partitioned nanoliter-scale droplets in oil emulsion. Each droplet contains a barcoded gel bead, a single cell, and enzyme Master Mix (10X Genomics) for probe pair ligation and gel bead primer barcode extension. The droplets in oil emulsion are place in a thermal cycler for 60 min at 25◦C, 45 min at 60◦C, and 20 min at 80◦C. The single cell- barcoded, ligated probe product undergo library preparation to be compatible with Illumina next- generation sequencing. The gene expression library derived from single cell-barcoded, ligated probe product were sequenced as paired-end 150 bp reads on the Illumina NovaSeq 6000 (Illumina) at the University of Colorado - Genomics Shared Resource (Aurora, CO, USA) at a depth of 20,000 reads per cell. The FindClusters algorithm was run on the PCs to identify clusters of cell populations. The DimPlot function was then used to create UMAPs stratified by condition, when applicable. Positive conserved cell type markers were identified using the FindAllMarkers function with minimum detection and log2-fold change (log2FC) thresholds set to 25%. The top marker genes by log2FC are presented in a table and visualized with dotplots and feature plots using the DotPlot and FeaturePlot functions. Genes that were differentially expressed (DE) across condition were identified for each cluster. DE was assessed at the cell level using the FindAllMarkers MAST Hurdle Approach and previously described thresholds. Genes were considered DE if Bonferroni- adjusted significance was less than 0.05. DE genes are presented in tables. Immunoblotting analysis: Cells with different treatments were harvested and lysed in RIPA buffer. Cell lysates were separated on SDS-PAGE gels and transferred to nitrocellulose membranes (Amersham™ Protran™, 0.2 μm). After blocking nonspecific bindings with blocking buffer (5% non-fat milk in TBST) for 45 minutes at room temperature, membranes were immunoblotted with primary antibodies 1.5 hours at room temperature. After, membranes were incubated with HRP-conjugated donkey anti-rabbit / sheep anti-mouse secondary antibody for 1 hour at room temperature. The protein bands were developed with SuperSingal™ west dura extended duration substrate (Thermo, lot#X8340749) and detected by ImageQuant™ LAS 4000 (GE healthcare) TFEA analysis: For each gene, the transcription start site (TSS) was identified using the GENCODE comprehensive gene annotation (version 35). Promoter regions were defined as 2000 base pairs (bp) upstream and 500 bp downstream of each TSS. Overlapping promoter regions were merged to create non-redundant gene promoter sets. Position weight matrices (PWMs) for human transcription factors were obtained from the JASPAR database. The FIMO tool from the MEME Suite was used to scan promoter sequences for potential binding sites for each transcription factor, with a p-value cutoff of 1e-4. For each transcription factor, an enrichment score was calculated using a hypergeometric test, comparing the overlap of genes with potential binding sites in their promoters and the gene set of interest. P-values were adjusted for multiple testing using the Benjamini-Hochberg procedure. Transcription factor enrichment analysis was performed using custom Python scripts, utilizing the SciPy and StatsModels libraries for statistical calculations and Matplotlib and Seaborn for data visualization. Example 15. Materials and Methods (Figure Series 4). RNA extraction: Total RNA was isolated from the samples using the TRIzol reagent (Invitrogen, Carlsbad, CA, USA) according to the manufacturer's protocol. Briefly, samples were homogenized in 1 ml of TRIzol reagent and incubated at room temperature for 5 minutes. Chloroform (200 µl) was added to the homogenate, shaken vigorously for 15 seconds, and allowed to stand at room temperature for 2-3 minutes. The mixture was then centrifuged at 12,000 g for 15 minutes at 4°C. The aqueous phase was transferred to a fresh tube and RNA was precipitated by adding an equal volume of isopropanol. After a 10-minute incubation at room temperature, the samples were centrifuged at 12,000 g for 10 minutes at 4°C. The RNA pellet was washed with 75% ethanol, air-dried, and resuspended in RNase-free water. The concentration and purity of the RNA were determined using a NanoDrop spectrophotometer (Thermo Fisher Scientific, Waltham, MA, USA). Quantitative real-time PCR: Quantitative real-time PCR (qRT-PCR) was performed using the Luna® Universal qPCR Master Mix (New England Biolabs, Ipswich, MA, USA) according to the manufacturer's instructions. Briefly, the 20 µl reaction volume consisted of 10 µl Luna Universal qPCR Master Mix, 1 µl of each forward and reverse primer (10 µM), 2 µl of template cDNA, and 6 µl of nuclease-free water. The reactions were run on a Real-Time PCR System (Applied Biosystems, Foster City, CA, USA) with the following thermal cycling conditions: initial denaturation at 95°C for 1 minute, followed by 40 cycles of denaturation at 95°C for 15 seconds, annealing at 60°C for 30 seconds, and extension at 72°C for 30 seconds. The expression of the target genes was normalized to the expression of the housekeeping gene, and the relative gene expression was calculated using the 2^-ΔΔCT method. Each sample was run in triplicate, and a no-template control was included to ensure specificity and absence of contamination. MicroScale Thermophoresis™: 45 μL of 200 nM protein was mixed with 45 μL of 100 nM RED-tris-NTA 2nd Generation dye (NanoTemper™ technologies). After mixing, sample was incubated for 30 minutes at room temperature in dark followed by 10 minutes 15000 g centrifugation at 4 °C. After centrifugation, sample was transferred into a new tube and loaded into capillaries (Monolit™ NT.115 Standard Treated Capillaries) and tested by Monolith™ NT.115 (NanoTemper™ technologies). Protein paragazole thiol crosslinking assay: 4 μg of protein was mixed with 4 μL of 10 mM H2O2 (MACRON FINE CHEMICALS™), 1 μL of 10 mM paragazole thiol and filled with phosphate buffer (200 mM, pH 7.0) up to 20 μL. After mixing, sample was incubated under room temperature in dark for 5 hours. Crosslinked protein was stored at -20 °C for future use. Recombinant His-tag PRDX6 purification: Protein purification was performed based on The QIAexpressionist™ (Qiagen™). Briefly, plasmid was transformed M10 competent cells that were inoculated with 6 mL culture medium containing ampicillin (100 μg / mL) and kanamycin (25 μg / mL), shaken overnight at 37. After overnight shaking, culture was added into 150 mL of prewarmed media (with antibiotics) with 1 mM Isopropyl β-D-1-thiogalactopyranoside (IPTG) and shaked for 5 hours at 37°C. After 5 hours shaking, culture was harvested by centrifugation at 4000 g for 20 minutes and pellet was sonicated on ice using ultrasonic cell disruptor (Microson™ , six 10s bursts at 20 W with a 10 second cooling period between each burst) in 5 mL lysis buffer (50 mM NaH2PO4, 300 mM NaCl, 10 mM imidazole, pH 8.0). Lysate was cleared by centrifugation at 10000 g for 20 minutes at 4°C, supernatant was mixed with 2 mL 50% NI-NTA slurry and mixture was incubated at 4°C for 1 hour with constant rocking (200 rpm). After rocking, mixture was loaded into a column with bottom outlet closed and bottom was opened once the mixture was settled down. Remained beads was washed twice with 5 mL wash buffer (50 mM NaH2PO4, 300 mM NaCl, 20 mM imidazole, pH 8.0) and eluted with 1 mL elution buffer twice (50 mM NaH2PO4, 300 mM NaCl, 250 mM imidazole, pH 8.0). Eluted protein was further buffer- exchanged with storage buffer (DPBS, 10% glycerol) using Amicon Ultra-4 Ultracel-5k (Millipore™) and protein was stored at 4°C for future use. Cellular thermal shift assay (CESTA): 2*106of HCT116 cells were treated with DMSO, 10μM MJ33, 100 nM largazole or 1 μM paragazole for 4 hours. After incubation, each set of cells was collected and washed with ice-cold D-PBS, then resuspended in 1 mL ice-cold D-PBS and aliquoted in 9 PCR tubes and heated at indicated temperature for 3 minutes using thermal cycler (BIO-RAD, T100™). After heating, cells were lysed by freeze-thaw under 80 °C and cell lysates were clarified by centrifugation at 15000 g for 10 minutes at 4 °C. Then supernatants were collected and analyzed by immunoblotting. Intact Mass Spectrometry Analysis: Intact mass spectrometry analysis was performed using Waters ACQUITY UPLC system coupled with a Waters Synapt G2 mass spectrometer. For liquid chromatography (LC), a Waters ACQUITY UPLC system equipped with a Protein BEH C4 VanGuard Pre-column (300Å, 1.7 µm, 2.1 mm X 5 mm) was used. A 10 µL injection was performed at a concentration of 0.1 mg / mL. The mobile phase A consisted of water with 0.1% formic acid, while the mobile phase B was acetonitrile with 0.1% formic acid. A 3-minute linear gradient from 3% to 85% B was used for elution of proteins from the column. The eluted proteins were then introduced into a Waters Synapt G2 mass spectrometer for intact mass analysis. The mass spectrometer parameters were set up following the manufacturer's guidelines and optimized for the detection of intact proteins. The raw data obtained from the mass spectrometer were processed and analyzed using Waters MassLynx software. The deconvolution of the raw spectra was performed using the MaxEnt1 algorithm provided by the software. All data analyses and interpretation were performed following the guidelines recommended for accurate intact mass analysis. PRDX6 activity quantification assay: 4 μg of purified PRDX6 protein was mixed with 4 μL of 10 mM H2O2(MACRON FINE CHEMICALS™) and filled with phosphate buffer (200 mM, pH 7.0) up to 20 μL. After mixing, sample was incubated under room temperature in dark for 30 minutes. After incubation, each 5 μL of sample was mixed with 150 μL of HRP buffer (phosphate buffer 200 mM, pH 7.0; horseradish peroxidase > 0.2 kU / L; 4-aminophenazone, 0.33 mM) and 50 μM of 8 mM 3,5-dichloro-2-hydroxybenzenesulfonic acid (DHBS) for 30 minutes under room temperature in dark. Mixture was tested for absorbance at 520 nm after incubation. Statistical analysis: Statistical significance was determined by Microsoft® Excel®. Data are represented as mean ± SD. Student’s t-test was used for statistical analysis for data and p-value < 0.05 was considered as statistically significant. Immunoblotting analysis: Cells with different treatments were harvested and lysed in RIPA buffer. Cell lysates were separated on SDS-PAGE gels and transferred to nitrocellulose membranes (Amersham™ Protran™, 0.2 μm). After blocking nonspecific bindings with blocking buffer (5% non-fat milk in TBST) for 45 minutes at room temperature, membranes were immunoblotted with primary antibodies 1.5 hours at room temperature. After, membranes were incubated with HRP-conjugated donkey anti-rabbit / sheep anti-mouse secondary antibody for 1 hour at room temperature. The protein bands were developed with SuperSingal™ west dura extended duration substrate (Thermo, lot#X8340749) and detected by ImageQuant™ LAS 4000 (GE healthcare) Example 16. Materials and Methods (Figure Series 5). Generation of cell lines: To generate MDA-MB-231 PRDX6-KD and MDA-MB-468 PRDX6-KD cell lines, WT MDA-MB-231 (ATCC) and WT MDA-MB-468 (ATCC) cells were transduced with lentiviral pLOK.1 vector expressing shRNA for each indicated gene from an U6 promoter (TRC#N0000052157) and selected for puromycin-positive cells using puromycin (2 μg / mL). To generate A223 PRDX6-KD, TCh3 PRDX6-KD and TAb2 PRDX6-KD cell lines, WT A223 (ATCC), WT TCh3 and WT TAb2 (ATCC) cells were transduced with lentiviral pLOK.1 vector expressing shRNA for each indicated gene from an U6 promoter (TRC#N0000101384) and selected for puromycin-positive cells using puromycin (2 μg / mL). IC50 assay: 4,000 cells were seeded into each well of 96-well plate. After 24 hours of incubation, DMEM was replaced by fresh DMEM with drug in serial-diluted manner. Cells were conducted and quantified as cell viability assay after 3 days treatment. Cell viability assay: After treatment, cells were washed by D-PBS twice and incubated with 1 mL of 4% formaldehyde in D-PBS under room temperature, 100 RPM shaking for 10 minutes (Thermo, MaxQ 2000). Cells were washed again with D-PBS after incubation and incubated with 1 mL of 0.05% crystal violet staining buffer (250 mL MeOH, 750 mL MiliQ water, 0.5g crystal violet) under room temperature, 100 RPM shaking for 10 minutes. Cells were washed with DI water and air dried for 24 hours. Dried stained samples were captured by camera (Nikon D5600, by the courtesy of Hongxuan Chen) and resolubilized using 6 mL of solubilization buffer (400 mL EtOH, 100 mL MeOH, 100 mL MiliQ water) under 4°C, 100 RPM shaking for 1 hour. Resolubilized samples were further quantified by plate reader (absorbance 530 nm, Molecular Devices SpectraMAX iD3). RNA extraction: Total RNA was isolated from the samples using the TRIzol reagent (Invitrogen, Carlsbad, CA, USA) according to the manufacturer's protocol. Briefly, samples were homogenized in 1 ml of TRIzol reagent and incubated at room temperature for 5 minutes. Chloroform (200 µl) was added to the homogenate, shaken vigorously for 15 seconds, and allowed to stand at room temperature for 2-3 minutes. The mixture was then centrifuged at 12,000 g for 15 minutes at 4°C. The aqueous phase was transferred to a fresh tube and RNA was precipitated by adding an equal volume of isopropanol. After a 10-minute incubation at room temperature, the samples were centrifuged at 12,000 g for 10 minutes at 4°C. The RNA pellet was washed with 75% ethanol, air-dried, and resuspended in RNase-free water. The concentration and purity of the RNA were determined using a NanoDrop spectrophotometer (Thermo Fisher Scientific, Waltham, MA, USA). Quantitative real-time PCR: Quantitative real-time PCR (qRT-PCR) was performed using the Luna® Universal qPCR Master Mix (New England Biolabs, Ipswich, MA, USA) according to the manufacturer's instructions. Briefly, the 20 µl reaction volume consisted of 10 µl Luna Universal qPCR Master Mix, 1 µl of each forward and reverse primer (10 µM), 2 µl of template cDNA, and 6 µl of nuclease-free water. The reactions were run on a Real-Time PCR System (Applied Biosystems, Foster City, CA, USA) with the following thermal cycling conditions: initial denaturation at 95°C for 1 minute, followed by 40 cycles of denaturation at 95°C for 15 seconds, annealing at 60°C for 30 seconds, and extension at 72°C for 30 seconds. The expression of the target genes was normalized to the expression of the housekeeping gene, and the relative gene expression was calculated using the 2^-ΔΔCT method. Each sample was run in triplicate, and a no-template control was included to ensure specificity and absence of contamination. Immunoblotting analysis: Cells with different treatments were harvested and lysed in RIPA buffer. Cell lysates were separated on SDS-PAGE gels and transferred to nitrocellulose membranes (Amersham™ Protran™, 0.2 μm). After blocking nonspecific bindings with blocking buffer (5% non-fat milk in TBST) for 45 minutes at room temperature, membranes were immunoblotted with primary antibodies 1.5 hours at room temperature. After, membranes were incubated with HRP-conjugated donkey anti-rabbit / sheep anti-mouse secondary antibody for 1 hour at room temperature. The protein bands were developed with SuperSingal™ west dura extended duration substrate (Thermo, lot#X8340749) and detected by ImageQuant™ LAS 4000 (GE healthcare) Example 17. Materials and Methods (Figure Series 6). TCGA analysis: Kaplan-Meier analysis and Log-rank statistics were performed using R (version 4.2.0). Survival analysis is based on two grouping methods: High-Prdx6 and Low-Prdx6 groups, determined by the median expression of Prdx6, and samples with significantly upregulated Prdx6 and downregulated Prdx6 groups in tumors. Overall Survival difference between two groups was evaluated using Kaplan-Meier analysis and verified by the Log-rank test. Statistical significance was defined as a p-value < 0.05. The gene expression matrix and clinical information of TCGA patient were downloaded from the UCSC Xena browser. Natural proliferation assay: 500 cells were seeded into each well of 96-well plate. After indicated duration of incubation, cells were conducted and quantified as cell viability assay.

[0002] TABLES Table 1.3 KLFs expression level in each cluster. (A) KLFs that are top100 upregulated in indicated clusters. (B) KLFs with more than 0.25-fold change in each cluster, both upregulated and downregulated, using differential expression analysis.

[0003] Table 5.1.1 Quantification of IC50 assay of Figure 5.1. IC50 was calculated using Quest Graph™ IC50 Calculator. AAT Bioquest. Non-significant p-value was labeled in red. Table 5.2 Quantification of IC50 assay of Figure 5.2. IC50 was calculated using Quest Graph™ IC50 Calculator. AAT Bioquest. Largazole data was retrieved from figure 5.1A and table 5.1. Non- significant p-value was labeled in red. SEQUENCE LISTING SEQ ID NO.1 DNA PRDX6 Homo Sapiens GCTTCTTCGCCAGAACCAACCGGTTGCTTGCTGTCCCAGCGGCGCCCCCTCATCACCGTCGCCATGCCCGGAGGTCT GCTTCTCGGGGACGTGGCTCCCAACTTTGAGGCCAATACCACCGTCGGCCGCATCCGTTTCCACGACTTTCTGGGAG ACTCATGGGGCATTCTCTTCTCCCACCCTCGGGACTTTACCCCAGTGTGCACCACAGAGCTTGGCAGAGCTGCAAAG CTGGCACCAGAATTTGCCAAGAGGAATGTTAAGTTGATTGCCCTTTCAATAGACAGTGTTGAGGACCATCTTGCCTG GAGCAAGGATATCAATGCTTACAATTGTGAAGAGCCCACAGAAAAGTTACCTTTTCCCATCATCGATGATAGGAATC GGGAGCTTGCCATCCTGTTGGGCATGCTGGATCCAGCAGAGAAGGATGAAAAGGGCATGCCTGTGACAGCTCGTGTG GTGTTTGTTTTTGGTCCTGATAAGAAGCTGAAGCTGTCTATCCTCTACCCAGCTACCACTGGCAGGAACTTTGATGA GATTCTCAGGGTAGTCATCTCTCTCCAGCTGACAGCAGAAAAAAGGGTTGCCACCCCAGTTGATTGGAAGGATGGGG ATAGTGTGATGGTCCTTCCAACCATCCCTGAAGAAGAAGCCAAAAAACTTTTCCCGAAAGGAGTCTTCACCAAAGAG CTCCCATCTGGCAAGAAATACCTCCGCTACACACCCCAGCCTTAAGTCTCTTGGAGAAGCTGGTGCTGTGAGCCAGA GGATGTCAGCTGCCAATTGTGTTTTCCTGCAGCAATTCCATAAACACATCCTGGTGTCATCACAGCCAAGGTTTTTA GGTTGCTATACCAATGGCTTATTAAATGAAAATGGCACTAAAAGTTTCTTGAGATTCTTTATACTCTCTGCCTTCAG CAATCAATTCCATTCATACATCAGCACTCTGCTGGTTCTGTTTGAAATATGTTCTGTATTTAAAACTCAAATCTTGT TGGATCTCTGCAGGGCTTGTGACCAATGAAGTCATATTTGTTGATGGTTGACAAAGCTTGCTTCACTCCATCAGAGA ATGACTATCAATTTTTTTTTAACTGTCCTATCACGTCCTCTCCTGTCACCCATTTTGAAGAGTGGCAGAACTTGAAG TTCAACTTCCTCTGTAAATATCCAAGTATAAAGCCCAGGAACTTCTAGAATAACCCAGATGCGCTTTAATTTTTTTT AATATGTTTTGATCACAGAACTTCTAGAATAACCCAGATGCTCTTTCATATTCTTTTAATACATCTTGATCACAGCT GGGGGAAAAAAAGCTTTTTAATTCTATACCTTCCTAGTAGATAAGTGAAGAGCAGGGAAAGAGACCTTTAAATATTT TGCTATAAAAAAATTTGTGATAAGTTTCTATCAAAATGGGGAGATTGCAGAAAAGGCTTCCCTTGGCTCCCAAGGAG GTGTAGCAGGTGTGAGCAATATTAGTGCCATGTGCCTTTCACACAGGGTTTGCATTTATCAGTCTGTTTTCCGATGA TGTGTACATGAAAGAGTACACCATGTGAAGAGAAGAGAGAATGATTGAAAATGTTTTAGTATAGAACTCTTCTTGCA GTGGGTTGCTATTTTCTAGATTTTACTTTTTAGGGAACAAAATAAAATCCTTTGTTAAAACTGGGTCAGAGAA SEQ ID NO.2 Amino Acid PRDX6 Homo Sapiens MPGGLLLGDVAPNFEANTTVGRIRFHDFLGDSWGILFSHPRDFTPVCTTELGRAAKLAPEFAKRNVKLIALSIDSVE DHLAWSKDINAYNCEEPTEKLPFPIIDDRNRELAILLGMLDPAEKDEKGMPVTARVVFVFGPDKKLKLSILYPATTG RNFDEILRVVISLQLTAEKRVATPVDWKDGDSVMVLPTIPEEEAKKLFPKGVFTKELPSGKKYLRYTPQP SEQ ID NO.3 Amino Acid PD1 precursor Homo Sapiens MQIPQAPWPVVWAVLQLGWRPGWFLDSPDRPWNPPTFSPALLVVTEGDNATFTCSFSNTSESFVLNWYRMSPSNQTD KLAAFPEDRSQPGQDCRFRVTQLPNGRDFHMSVVRARRNDSGTYLCGAISLAPKAQIKESLRAELRVTERRAEVPTA HPSPSPRPAGQFQTLVVGVVGGLLGSLVLLVWVLAVICSRAARGTIGARRTGQPLKEDPSAVPVFSVDYGELDFQWR EKTPEPPVPCVPEQTEYATIVFPSGMGTSSPARRGSADGPRSAQPLRPEDGHCSWPL SEQ ID NO.4 Amino Acid PD1 isoform X Homo Sapiens MQIPQAPWPVVWAVLQLGWRPGWFLDSPDRPWNPPTFSPALLVVTEGDNATFTCSFSNTSESFVLNWYRMSPSNQTD KLAAFPEDRSQPGQDCRFRVTQLPNGRDFHMSVVRARRNDSGTYLCGAISLAPKAQIKESLRAELRVTERRAEVPTA HPSPSPRPAGQFQTLVVGVVGGLLGSLVLLVWVLAVICSRAARG SEQ ID NO.5 Amino Acid PD-L1 Homo Sapiens MRIFAVFIFMTYWHLLNAFTVTVPKDLYVVEYGSNMTIECKFPVEKQLDLAALIVYWEMEDKNIIQFVHG EEDLKVQHSSYRQRARLLKDQLSLGNAALQITDVKLQDAGVYRCMISYGGADYKRITVKVNAPYNKINQR ILVVDPVTSEHELTCQAEGYPKAEVIWTSSDHQVLSGKTTTTNSKREEKLFNVTSTLRINTTTNEIFYCT FRRLDPEENHTAELVIPELPLAHPPNERTHLVILGAILLCLGVALTFIFRLRKGRMMDVKKCGIQDTNSK KQSDTHLEET SEQ ID NO.6 DNA PRDX6, mRNA Homo Sapiens ATGCCCGGAGGTCTGCTTCTCGGGGACGTGGCTCCCAACTTTGAGGCCAATACCACCGTCGGCCGCATCC GTTTCCACGACTTTCTGGGAGACTCATGGGGCATTCTCTTCTCCCACCCTCGGGACTTTACCCCAGTGTG CACCACAGAGCTTGGCAGAGCTGCAAAGCTGGCACCAGAATTTGCCAAGAGGAATGTTAAGTTGATTGCC CTTTCAATAGACAGTGTTGAGGACCATCTTGCCTGGAGCAAGGATATCAATGCTTACAATTGTGAAGAGC CCACAGAAAAGTTACCTTTTCCCATCATCGATGATAGGAATCGGGAGCTTGCCATCCTGTTGGGCATGCT GGATCCAGCAGAGAAGGATGAAAAGGGCATGCCTGTGACAGCTCGTGTGGTGTTTGTTTTTGGTCCTGAT AAGAAGCTGAAGCTGTCTATCCTCTACCCAGCTACCACTGGCAGGAACTTTGATGAGATTCTCAGGGTAG TCATCTCTCTCCAGCTGACAGCAGAAAAAAGGGTTGCCACCCCAGTTGATTGGAAGGATGGGGATAGTGT GATGGTCCTTCCAACCATCCCTGAAGAAGAAGCCAAAAAACTTTTCCCGAAAGGAGTCTTCACCAAAGAG CTCCCATCTGGCAAGAAATACCTCCGCTACACACCCCAGCCTTAA SEQ ID NO.7 RNA Pan PRDX6 siRNA Artificial GCUGUCUAUCCUCUACCCA SEQ ID NO.8 RNA hPRDX6 siRNA Artificial CCCUUUCAAUAGACAGUGUU SEQ ID NO.9 RNA KKV140 Artificial GACAGUGUUGAGGACCAUCUU

Claims

CLAIMS What is claimed is:

1. A pharmaceutical composition for the treatment of cancer in a subject in need thereof, comprising a therapeutically effective amount of a histone deacetylase inhibitor (HDACI), a Peroxiredoxin 6 (PRDX6) inhibitor, and a pharmaceutically acceptable carrier.

2. The composition of claim 1, wherein said HDACI is selected from: OKI-179, largazole, and OKI-5, or a combination of the same.

3. The composition of claim 1, wherein said HDACI is selected from: Vorinostat, Romidepsin (Isodax), SAHA (Vironostat), PDX101 (Belinostat), Panobinostat, Eintinostat, TSA (Trichostatin), OKI-5 (Paragazole), Largazole, OKI-179, and chidamide (CS055), or a combination of the same.

4. The composition of claim 1, wherein the PRDX6 inhibitor is selected from: a small-inhibitory RNA (siRNA), short hairpin RNA (shRNA), bifunctional RNA, antisense oligonucleotide, anti- PRDX6 antibody or functional fragment thereof, ribozyme, deoxyribozyme, aptamer, small molecule or gene therapy that knocks out PRDX6, MJ33, or an oligonucleotide according to SEQ ID NO’s.7-9.

5. The composition of claim 1, wherein said subject is a human.

6. A method of treating cancer in a subject in need thereof, comprising contacting a cancer cell with a therapeutically effective amount of a histone deacetylase inhibitor (HDACI), and a Peroxiredoxin 6 (PRDX6) inhibitor.

7. The method of claim 6, wherein said HDACI is selected from: OKI-179, largazole, and OKI-5, or a combination of the same.

8. The method of claim 6, wherein said HDACI is selected from: Vorinostat, Romidepsin (Isodax), SAHA (Vironostat), PDX101 (Belinostat), Panobinostat, Eintinostat, TSA (Trichostatin), OKI-5 (Paragazole), Largazole, OKI-179, and chidamide (CS055), or a combination of the same.

9. The method of claim 6, wherein the PRDX6 inhibitor is selected from: a small-inhibitory RNA (siRNA), short hairpin RNA (shRNA), bifunctional RNA, antisense oligonucleotide, anti-PRDX6 antibody or functional fragment thereof, ribozyme, deoxyribozyme, aptamer, small molecule or gene therapy that knocks out PRDX6, MJ33, or an oligonucleotide according to SEQ ID NO’s.7- 9.

10. The method of claim 6, wherein said subject is a human.

11. A method of treating cancer comprising the step of administering a therapeutically effective amount of a histone deacetylase inhibitor (HDACI) to a subject in need thereof, wherein the levels of Peroxiredoxin 6 (PRDX6) in the cancer cell of the subject are at a level, when compared to a reference level, indicative that the subject will respond to the administration of a therapeutically effective amount the HDACI.

12. The method of claim 11, wherein said HDACI is selected from: OKI-179, largazole, and OKI- 5, or a combination of the same.

13. The method of claim 11, wherein said HDACI is selected from: Vorinostat, Romidepsin (Isodax), SAHA (Vironostat), PDX101 (Belinostat), Panobinostat, Eintinostat, TSA (Trichostatin), OKI-5 (Paragazole), Largazole, OKI-179, and chidamide (CS055), or a combination of the same.

14. The method of claim 11, further comprising administering a therapeutically effective amount of PRDX6 inhibitor.

15. The method of claim 14, wherein the therapeutically effective amount of PRDX6 inhibitor comprises an amount of the PRDX6 inhibitor causes the levels of PRDX6 in the cancer cell of thesubject are at a level, when compared to a reference level, which is indicative that the subject will respond to the administration of the HDACI.

16. The method of claim 14, wherein the PRDX6 inhibitor is selected from: a small-inhibitory RNA (siRNA), short hairpin RNA (shRNA), bifunctional RNA, antisense oligonucleotide, anti- PRDX6 antibody or functional fragment thereof, ribozyme, deoxyribozyme, aptamer, small molecule or gene therapy that knocks out PRDX6, MJ33, or an oligonucleotide according to SEQ ID NO’s.7-9.

17. The method of claim 11, wherein said subject is a human.

18. The method of claim 11, further comprising determining the level of PRDX6 n the cancer cell of the subject or a reference level is performed prior to administration of the HDACI, by Northern blot analysis, Western blot analysis, quantitative or semi-quantitative reverse transcription- polymerase chain reaction (RT-PCR), ligase chain reaction (LCR), transcription-mediated amplification (TMA), strand displacement amplification (SDA), and nucleic acid sequence-based amplification (NASBA).

19. The method of claim 18, wherein the levels of PRDX6 are determined my measuring levels of PRDX6 RNA transcripts.

20. A method for determining if a cancer patient is predicted to respond to the administration of histone deacetylase inhibitor (HDACI) therapy, the method comprising: − detecting in a sample of cancer cells from the patient, a level of gene expression of Peroxiredoxin 6 (PRDX6), wherein the expression levels of the PRDX6 are indicative of whether the patient will respond to the administration of a therapeutically effective amount of at least one HDACI.

21. The method of claim 20, wherein said HDACI is selected from: OKI-179, largazole, and OKI- 5, or a combination of the same.

22. The method of claim 20, wherein said HDACI is selected from: Vorinostat, Romidepsin (Isodax), SAHA (Vironostat), PDX101 (Belinostat), Panobinostat, Eintinostat, TSA (Trichostatin), OKI-5 (Paragazole), Largazole, OKI-179, and chidamide (CS055), or a combination of the same.

23. The method of claim 20, wherein said subject is a human.

24. The method of claim 20, further comprising determining the level of PRDX6 in the cancer cells of the subject or a reference level is performed prior to administration of the HDACI, by Northern blot analysis, Western blot analysis, quantitative or semi-quantitative reverse transcription-polymerase chain reaction (RT-PCR), ligase chain reaction (LCR), transcription- mediated amplification (TMA), strand displacement amplification (SDA), and nucleic acid sequence-based amplification (NASBA).

25. The method of claim 24, wherein the levels of PRDX6 are determined my measuring levels of PRDX6 RNA transcripts.

26. A method of assessing the efficacy or effectiveness of a HDACI inhibitor therapy treatment being administered to a cancer subject, the method comprising: - measuring the activity level of a pharmacodynamic biomarker PRDX6 in a first sample obtained from the subject at a time t0; - co-administering an HDACI and / or a PRDX6 inhibitor after said time t0; - measuring the activity level of the pharmacodynamic biomarker PRDX6 in a second sample obtained from the subject at time t1; and - wherein a change in the activity level of the pharmacodynamic biomarker PRDX6 in the second sample relative to the first sample is an indication that the HDACI treatment is effective for treating cancer in the subject.

27. The method of claim 26, wherein said HDACI is selected from: OKI-179, largazole, and OKI- 5, or a combination of the same.

28. The method of claim 26, wherein said HDACI is selected from: Vorinostat, Romidepsin (Isodax), SAHA (Vironostat), PDX101 (Belinostat), Panobinostat, Eintinostat, TSA (Trichostatin), OKI-5 (Paragazole), Largazole, OKI-179, and chidamide (CS055), or a combination of the same.

29. The method of claim 26, wherein the PRDX6 inhibitor is selected from: a small-inhibitory RNA (siRNA), short hairpin RNA (shRNA), bifunctional RNA, antisense oligonucleotide, anti- PRDX6 antibody or functional fragment thereof, ribozyme, deoxyribozyme, aptamer, small molecule or gene therapy that knocks out PRDX6, MJ33, or an oligonucleotide according to SEQ ID NO’s.7-9.

30. A method of treating a subject having a cancer comprising: a) determining the level of PRDX6 in: i) a test sample obtained from the subject, and ii) optionally a control sample; b) optionally obtaining a reference value corresponding to a level of PRDX6, wherein the level of PRDX6 in the test sample relative to the control sample or the reference value indicates whether the subject will respond to the administration of a therapeutically effective amount of at least one HDACI; and, c) identifying the subject as having a cancer involving a level of PRDX6 indictive that the subject will respond to the HDACI based on the level of PRDX6 in the test sample, and administering an effective amount of a HDACI to the subject to treat the cancer, or d) identifying the subject as having the cancer not involving a level of PRDX6 indictive that the subject will not respond to the HDACI based on the level of PRDX6 in the test sample, and withholding the administration of the HDACI to the subject, and optionally, administering a cancer therapy other than the HDACI to the subject to treat the cancer.

31. The method of claim 30, wherein the control sample is obtained from: a) an individual belonging to the same species as the subject and not having cancer, or b) an individual belonging to the same species as the subject and known to have a cancer having a level of PRDX6 indictive that the subject will respond to the HDACI, orc) an individual belonging to the same species as the subject and known to have a cancer having a level of PRDX6 indictive that the subject will not respond to the HDACI.

32. The method of claim 30, wherein the reference value corresponds to the level of PRDX6 indictive that the subject will respond to the HDACI, or a level of PRDX6 indictive that the subject will not respond to the HDACI.

33. The method of claim 30, wherein said HDACI is selected from: OKI-179, largazole, and OKI- 5, or a combination of the same.

34. The method of claim 30, wherein said HDACI is selected from: Vorinostat, Romidepsin (Isodax), SAHA (Vironostat), PDX101 (Belinostat), Panobinostat, Eintinostat, TSA (Trichostatin), OKI-5 (Paragazole), Largazole, OKI-179, and chidamide (CS055), or a combination of the same.

35. The method of claim 30, further comprising administering to the subject a therapeutically effective amount of a PRDX6 inhibitor.

36. The method of claim 35, wherein the PRDX6 inhibitor is selected from: a small-inhibitory RNA (siRNA), short hairpin RNA (shRNA), bifunctional RNA, antisense oligonucleotide, anti- PRDX6 antibody or functional fragment thereof, ribozyme, deoxyribozyme, aptamer, small molecule or gene therapy that knocks out PRDX6, MJ33, or an oligonucleotide according to SEQ ID NO’s.7-9.

37. The method of claim 30, wherein the step of determining the level of PRDX6 is performed by Northern blot analysis, Western blot analysis, quantitative or semi-quantitative reverse transcription-polymerase chain reaction (RT-PCR), ligase chain reaction (LCR), transcription- mediated amplification (TMA), strand displacement amplification (SDA), and nucleic acid sequence-based amplification (NASBA).

38. The method of claim 30, wherein the subject is a human.

39. The method of claim 30, wherein the levels of PRDX6 are determined my measuring levels of PRDX6 RNA transcripts in the test sample and / or control sample.

40. A method for sensitizing a cancer cell to a Programmed death-1 (PD1) and / or a Programmed death ligand-1 (PD-L1) inhibitor, comprising contacting a cancer cell with a therapeutically effective amount of a Peroxiredoxin 6 (PRDX6) inhibitor, a histone deacetylase inhibitor (HDACI), or a combination of the same.

41. The method of claim 40, further comprising the step of contacting the cancer cell with a PD1 inhibitor or a PD-L1 inhibitor.

42. The method of claim 41, wherein the PD1 inhibitor is selected from: Pembrolizumab, Nivolumab, Cemiplimab, Toripalimab, Retifanlimab, Dostarlimab, a small-inhibitory RNA (siRNA), short hairpin RNA (shRNA), bifunctional RNA, antisense oligonucleotide, anti- PD1 antibody or functional fragment thereof, a ribozyme, a deoxyribozyme, or an aptamer.

43. The method of claim 41, wherein the PD-L1 inhibitor is selected from: Atezolizumab, Avelumab, Durvalumab, a small-inhibitory RNA (siRNA), short hairpin RNA (shRNA), bifunctional RNA, antisense oligonucleotide, anti-PD-L1 antibody or functional fragment thereof, a ribozyme, a deoxyribozyme, or an aptamer.

44. The method of claim 40, wherein the PRDX6 inhibitor is selected from: a small-inhibitory RNA (siRNA), short hairpin RNA (shRNA), bifunctional RNA, antisense oligonucleotide, anti- PRDX6 antibody or functional fragment thereof, ribozyme, deoxyribozyme, aptamer, small molecule or gene therapy that knocks out PRDX6.

45. The method of claim 40, wherein the PRDX6 inhibitor is selected from: SEQ ID NO’s.7-9.

46. The method of claim 40, wherein the HDACI is selected from: Vorinostat, Romidepsin (Isodax), SAHA (Vironostat), PDX101 (Belinostat), Panobinostat, Eintinostat, TSA(Trichostatin), OKI-5 (Paragazole), Largazole, OKI-179, and chidamide (CS055), or a combination of the same.

47. The method of claim 40, wherein said subject is a human.

48. The method of claim 40, wherein the cancer is selected from: Head and neck cancer; lung cancer such as non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC); mediastinal neoplasms such as neurogenic tumors and mesenchymal tumors; gastrointestinal (GI) cancers such as esophagus, Cancers of the stomach (stomach cancer), pancreas, liver and bile ducts (including hepatocellular carcinoma (HCC)), and small and large intestine (including colorectal cancer); prostate cancer; testicular cancer; gynecological cancer, ovary Cancer; breast cancer such as breast cancer, hormone receptor positive breast cancer, Her2 positive breast cancer, and triple negative breast cancer; endocrine cancer; soft tissue sarcoma such as fibrosarcoma, rhabdomyosarcoma, angiosarcoma, Kaposi sarcoma; Osteosarcoma, myeloma, osteosarcoma, Ewing tumor, fibrosarcoma, osteochondroma, osteoblastoma, and chondroblastoma; mesothelioma; skin cancer, basal cell carcinoma, squamous cell carcinoma, Merkel Cell carcinoma and melanoma; central nervous system Neoplasms of the brain, such as astrocytoma, glioblastoma, glioma, neuroblastoma, and retinoblastoma; lymphoma and leukemia, such as B-cell non-Hodgkin lymphoma (NHL), T-cell non-Hodgkin Lymphoma, chronic B-cell lymphocytic leukemia (B- CLL), chronic T-cell lymphocytic leukemia (T-CLL), Hodgkin's disease (HD), large granular lymphocytic leukemia (LGL), chronic myeloid leukemia (CML), Acute myeloid / myelocytic leukemia (AML), acute lymphoid / lymphoblastic leukemia (ALL), multiple myeloma (MM), plasmacytoma, and myelodysplastic syndrome (MDS).

49. The method of claim 40, wherein the cancer is non-small cell lung cancer (NSCLC).

50. The method of claim 40, further comprising the step of administering a cytotoxic T-lymphocyte associated protein 4 (CTLA-4) inhibitor.

51. The method of claim 50, wherein said CTLA-4 inhibitor is selected from: Ipilimumab, tremelimumab, a small-inhibitory RNA (siRNA), short hairpin RNA (shRNA), bifunctional RNA,antisense oligonucleotide, anti-CTLA-4 antibody or functional fragment thereof, a ribozyme, a deoxyribozyme, or an aptamer.

52. The method of claim 40, further comprising the step of administering a lymphocyte-activation gene 3 (LAG-3) inhibitor.

53. The method of claim 40, wherein said LAG-3 inhibitor is selected from: Relatlimab, a small- inhibitory RNA (siRNA), short hairpin RNA (shRNA), bifunctional RNA, antisense oligonucleotide, anti-LAG-3 antibody or functional fragment thereof, a ribozyme, a deoxyribozyme, or an aptamer.

54. A pharmaceutical composition for sensitizing a cancer cell to a programmed death-1 (PD1) and / or a programmed death ligand-1 (PD-L1) inhibitor, comprising a therapeutically effective amount of a PD1 inhibitor, a Peroxiredoxin 6 (PRDX6) inhibitor, a histone deacetylase inhibitor (HDACI), and a pharmaceutically acceptable carrier.

55. The composition of claim 54, wherein the PD1 inhibitor is selected from: Pembrolizumab, Nivolumab, Cemiplimab, Toripalimab, Retifanlimab, Dostarlimab, a small-inhibitory RNA (siRNA), short hairpin RNA (shRNA), bifunctional RNA, antisense oligonucleotide, anti- PD1 antibody or functional fragment thereof, a ribozyme, a deoxyribozyme, or an aptamer.

56. The composition of claim 54, wherein the PD-L1 inhibitor is selected from: Atezolizumab, Avelumab, Durvalumab, a small-inhibitory RNA (siRNA), short hairpin RNA (shRNA), bifunctional RNA, antisense oligonucleotide, anti-PD-L1 antibody or functional fragment thereof, a ribozyme, a deoxyribozyme, or an aptamer.

57. The composition of claim 54, wherein the PRDX6 inhibitor is selected from: a small-inhibitory RNA (siRNA), short hairpin RNA (shRNA), bifunctional RNA, antisense oligonucleotide, anti- PRDX6 antibody or functional fragment thereof, ribozyme, deoxyribozyme, aptamer, small molecule or gene therapy that knocks out PRDX6.

58. The composition of claim 54, wherein the PRDX6 inhibitor is selected from: SEQ ID NO’s. 7-9.

59. The composition of claim 54, wherein the HDACI is selected from: Vorinostat, Romidepsin (Isodax), SAHA (Vironostat), PDX101 (Belinostat), Panobinostat, Eintinostat, TSA (Trichostatin), OKI-5 (Paragazole), Largazole, OKI-179, and chidamide (CS055), or a combination of the same.

60. The composition of claim 54, wherein said subject is a human.

61. The composition of claim 54, wherein the cancer is selected from: Head and neck cancer; lung cancer such as non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC); mediastinal neoplasms such as neurogenic tumors and mesenchymal tumors; gastrointestinal (GI) cancers such as esophagus, Cancers of the stomach (stomach cancer), pancreas, liver and bile ducts (including hepatocellular carcinoma (HCC)), and small and large intestine (including colorectal cancer); prostate cancer; testicular cancer; gynecological cancer, ovary Cancer; breast cancer such as breast cancer, hormone receptor positive breast cancer, Her2 positive breast cancer, and triple negative breast cancer; endocrine cancer; soft tissue sarcoma such as fibrosarcoma, rhabdomyosarcoma, angiosarcoma, Kaposi sarcoma; Osteosarcoma, myeloma, osteosarcoma, Ewing tumor, fibrosarcoma, osteochondroma, osteoblastoma, and chondroblastoma; mesothelioma; skin cancer, basal cell carcinoma, squamous cell carcinoma, Merkel Cell carcinoma and melanoma; central nervous system Neoplasms of the brain, such as astrocytoma, glioblastoma, glioma, neuroblastoma, and retinoblastoma; lymphoma and leukemia, such as B-cell non-Hodgkin lymphoma (NHL), T-cell non-Hodgkin Lymphoma, chronic B-cell lymphocytic leukemia (B- CLL), chronic T-cell lymphocytic leukemia (T-CLL), Hodgkin's disease (HD), large granular lymphocytic leukemia (LGL), chronic myeloid leukemia (CML), Acute myeloid / myelocytic leukemia (AML), acute lymphoid / lymphoblastic leukemia (ALL), multiple myeloma (MM), plasmacytoma, and myelodysplastic syndrome (MDS).

62. The composition of claim 54, wherein the cancer is non-small cell lung cancer (NSCLC).

63. The composition of claim 54, further comprising a cytotoxic T-lymphocyte associated protein 4 (CTLA-4) inhibitor.

64. The composition of claim 63, wherein said CTLA-4 inhibitor is selected from: Ipilimumab, tremelimumab, a small-inhibitory RNA (siRNA), short hairpin RNA (shRNA), bifunctional RNA, antisense oligonucleotide, anti-CTLA-4 antibody or functional fragment thereof, a ribozyme, a deoxyribozyme, or an aptamer.

65. The composition of claim 54, further comprising a lymphocyte-activation gene 3 (LAG-3) inhibitor.

66. The composition of claim 54, wherein said CTLA-4 inhibitor is selected from: Relatlimab, a small-inhibitory RNA (siRNA), short hairpin RNA (shRNA), bifunctional RNA, antisense oligonucleotide, anti-LAG-3 antibody or functional fragment thereof, a ribozyme, a deoxyribozyme, or an aptamer.

67. A method of treating cancer in a subject in need thereof, comprising contacting a cancer cell with a therapeutically effective amount of a Peroxiredoxin 6 (PRDX6) inhibitor.

68. The method of claim 67, wherein the PRDX6 inhibitor is selected from: a small-inhibitory RNA (siRNA), short hairpin RNA (shRNA), bifunctional RNA, antisense oligonucleotide, anti- PRDX6 antibody or functional fragment thereof, ribozyme, deoxyribozyme, aptamer, small molecule or gene therapy that knocks out PRDX6.

69. The method of claim 67, wherein the PRDX6 inhibitor is selected from: SEQ ID NO’s.7-9.

70. The method of claim 67, wherein said subject is a human.

71. The method of claim 67, wherein the cancer is selected from: head and neck squamous cell carcinoma (HNSCC), adrenocortical carcinoma (ACC), breast invasive carcinoma (BRCA),kidney renal papillary cell carcinoma (KIRP), brain lower grade glioma (LGG), lung adenocarcinoma (LUAD), and uterine corpus endometrial carcinoma (UCEC).

72. A method for sensitizing a cancer cell to a programmed death-1 (PD1) and / or a programmed death ligand-1 (PD-L1) inhibitor, contacting a cancer cell with a therapeutically effective amount of a Peroxiredoxin 6 (PRDX6) inhibitor.

73. The method of claim 72, further comprising the step of contacting the cancer cell with a PD1 inhibitor or a PD-L1 inhibitor.

74. The method of claim 73, wherein the PD1 inhibitor is selected from: Pembrolizumab, Nivolumab, Cemiplimab, Toripalimab, Retifanlimab, Dostarlimab, a small-inhibitory RNA (siRNA), short hairpin RNA (shRNA), bifunctional RNA, antisense oligonucleotide, anti- PD1 antibody or functional fragment thereof, a ribozyme, a deoxyribozyme, or an aptamer.

75. The method of claim 73, wherein the PD-L1 inhibitor is selected from: Atezolizumab, Avelumab, Durvalumab, a small-inhibitory RNA (siRNA), short hairpin RNA (shRNA), bifunctional RNA, antisense oligonucleotide, anti-PD-L1 antibody or functional fragment thereof, a ribozyme, a deoxyribozyme, or an aptamer.

76. The method of claim 72, wherein the PRDX6 inhibitor is selected from: a small-inhibitory RNA (siRNA), short hairpin RNA (shRNA), bifunctional RNA, antisense oligonucleotide, anti- PRDX6 antibody or functional fragment thereof, ribozyme, deoxyribozyme, aptamer, small molecule or gene therapy that knocks out PRDX6.

77. The method of claim 72, wherein the PRDX6 inhibitor is selected from: SEQ ID NO’s.7-9.

78. The method of claim 72, wherein said subject is a human.

79. The method of claim 72, wherein the cancer is selected from: Head and neck cancer; lung cancer such as non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC);mediastinal neoplasms such as neurogenic tumors and mesenchymal tumors; gastrointestinal (GI) cancers such as esophagus, Cancers of the stomach (stomach cancer), pancreas, liver and bile ducts (including hepatocellular carcinoma (HCC)), and small and large intestine (including colorectal cancer); prostate cancer; testicular cancer; gynecological cancer, g ovary Cancer; breast cancer such as breast cancer, hormone receptor positive breast cancer, Her2 positive breast cancer, and triple negative breast cancer; endocrine cancer; soft tissue sarcoma such as fibrosarcoma, rhabdomyosarcoma, angiosarcoma, Kaposi sarcoma; Osteosarcoma, myeloma, osteosarcoma, Ewing tumor, fibrosarcoma, osteochondroma, osteoblastoma, and chondroblastoma; mesothelioma; skin cancer, basal cell carcinoma, squamous cell carcinoma, Merkel Cell carcinoma and melanoma; central nervous system Neoplasms of the brain, such as astrocytoma, glioblastoma, glioma, neuroblastoma, and retinoblastoma; lymphoma and leukemia, such as B-cell non-Hodgkin lymphoma (NHL), T-cell non-Hodgkin Lymphoma, chronic B-cell lymphocytic leukemia (B- CLL), chronic T-cell lymphocytic leukemia (T-CLL), Hodgkin's disease (HD), large granular lymphocytic leukemia (LGL), chronic myeloid leukemia (CML), Acute myeloid / myelocytic leukemia (AML), acute lymphoid / lymphoblastic leukemia (ALL), multiple myeloma (MM), plasmacytoma, and myelodysplastic syndrome (MDS).

80. The method of claim 72, wherein the cancer is non-small cell lung cancer (NSCLC).

81. A method of treating cancer comprising the step of administering a therapeutically effective amount of a PD1 or PD-L1 inhibitor to a subject in need thereof, wherein the levels of Peroxiredoxin 6 (PRDX6) in the cancer cell of the subject are at a level, when compared to a reference level, indicative that the subject will respond to the administration of a therapeutically effective amount the a PD1 or PD-L1 inhibitor.

82. The method of claim 81, wherein the PD1 inhibitor is selected from: Pembrolizumab, Nivolumab, Cemiplimab, Toripalimab, Retifanlimab, Dostarlimab, a small-inhibitory RNA (siRNA), short hairpin RNA (shRNA), bifunctional RNA, antisense oligonucleotide, anti-PD1 antibody or functional fragment thereof, a ribozyme, a deoxyribozyme, or an aptamer.

83. The method of claim 81, wherein the PD-L1 inhibitor is selected from: Atezolizumab, Avelumab, Durvalumab, a small-inhibitory RNA (siRNA), short hairpin RNA (shRNA), bifunctional RNA, antisense oligonucleotide, anti- PD-L1 antibody or functional fragment thereof, a ribozyme, a deoxyribozyme, or an aptamer.

84. The method of claim 81, wherein said subject is a human.

85. The method of claim 81, wherein the cancer is selected from: Head and neck cancer; lung cancer such as non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC); mediastinal neoplasms such as neurogenic tumors and mesenchymal tumors; gastrointestinal (GI) cancers such as esophagus, Cancers of the stomach (stomach cancer), pancreas, liver and bile ducts (including hepatocellular carcinoma (HCC)), and small and large intestine (including colorectal cancer); prostate cancer; testicular cancer; gynecological cancer, ovary Cancer; breast cancer such as breast cancer, hormone receptor positive breast cancer, Her2 positive breast cancer, and triple negative breast cancer; endocrine cancer; soft tissue sarcoma such as fibrosarcoma, rhabdomyosarcoma, angiosarcoma, Kaposi sarcoma; Osteosarcoma, myeloma, osteosarcoma, Ewing tumor, fibrosarcoma, osteochondroma, osteoblastoma, and chondroblastoma; mesothelioma; skin cancer, basal cell carcinoma, squamous cell carcinoma, Merkel Cell carcinoma and melanoma; central nervous system Neoplasms of the brain, such as astrocytoma, glioblastoma, glioma, neuroblastoma, and retinoblastoma; lymphoma and leukemia, such as B-cell non-Hodgkin lymphoma (NHL), T-cell non-Hodgkin Lymphoma, chronic B-cell lymphocytic leukemia (B- CLL), chronic T-cell lymphocytic leukemia (T-CLL), Hodgkin's disease (HD), large granular lymphocytic leukemia (LGL), chronic myeloid leukemia (CML), Acute myeloid / myelocytic leukemia (AML), acute lymphoid / lymphoblastic leukemia (ALL), multiple myeloma (MM), plasmacytoma, and myelodysplastic syndrome (MDS).

86. The method of claim 81, wherein the cancer is non-small cell lung cancer (NSCLC).

87. The method of claim 81, further comprising administering a therapeutically effective amount of PRDX6 inhibitor.

88. The method of claim 87, wherein the therapeutically effective amount of PRDX6 inhibitor comprises an amount of the PRDX6 inhibitor causes the levels of PRDX6 in the cancer cell of the subject are at a level, when compared to a reference level, which is indicative that the subject will respond to the administration of the PD1 or PD-L1 inhibitor.

89. The method of claim 81, wherein the PRDX6 inhibitor is selected from: a small-inhibitory RNA (siRNA), short hairpin RNA (shRNA), bifunctional RNA, antisense oligonucleotide, anti- PRDX6 antibody or functional fragment thereof, ribozyme, deoxyribozyme, aptamer, small molecule or gene therapy that knocks out PRDX6.

90. The method of claim 81, further comprising determining the level of PRDX6 n the cancer cell of the subject or a reference level is performed prior to administration of the HDACI, by Northern blot analysis, Western blot analysis, quantitative or semi-quantitative reverse transcription- polymerase chain reaction (RT-PCR), ligase chain reaction (LCR), transcription-mediated amplification (TMA), strand displacement amplification (SDA), and nucleic acid sequence-based amplification (NASBA).

91. The method of claim 190, wherein the levels of PRDX6 are determined my measuring levels of PRDX6 RNA transcripts.

92. A method of treating a subject having a cancer comprising: a) determining the level of PRDX6 in: i) a test sample obtained from the subject, and ii) optionally a control sample; b) optionally obtaining a reference value corresponding to a level of PRDX6, wherein the level of PRDX6 in the test sample relative to the control sample or the reference value indicates whether the subject will respond to the administration of a therapeutically effective amount of at least one PD1 or PD-L1 inhibitor; and, c) identifying the subject as having a cancer involving a level of PRDX6 indictive that the subject will respond to the PD1 or PD-L1 inhibitor based on the level of PRDX6 in the test sample,and administering an effective amount of a PD1 or PD-L1 inhibitor to the subject to treat the cancer, or d) identifying the subject as having the cancer not involving a level of PRDX6 indictive that the subject will not respond to the PD1 or PD-L1 inhibitor based on the level of PRDX6 in the test sample, and withholding the administration of the PD1 or PD-L1 inhibitor to the subject, and optionally, administering a cancer therapy other than the PD1 or PD-L1 inhibitor to the subject to treat the cancer.

93. The method of claim 92, wherein the control sample is obtained from: a) an individual belonging to the same species as the subject and not having cancer, or b) an individual belonging to the same species as the subject and known to have a cancer having a level of PRDX6 indictive that the subject will respond to the PD1 or PD-L1 inhibitor, or c) an individual belonging to the same species as the subject and known to have a cancer having a level of PRDX6 indictive that the subject will not respond to the PD1 or PD-L1 inhibitor.

94. The method of claim 92, wherein the reference value corresponds to the level of PRDX6 indictive that the subject will respond to the PD1 or PD-L1 inhibitor, or a level of PRDX6 indictive that the subject will not respond to the PD1 or PD-L1 inhibitor.

95. The method of claim 92, wherein the PD1 inhibitor is selected from: Pembrolizumab, Nivolumab, Cemiplimab, Toripalimab, Retifanlimab, Dostarlimab, a small-inhibitory RNA (siRNA), short hairpin RNA (shRNA), bifunctional RNA, antisense oligonucleotide, anti-PD1 antibody or functional fragment thereof, a ribozyme, a deoxyribozyme, or an aptamer.

96. The method of claim 92, wherein the PD-L1 inhibitor is selected from: Atezolizumab, Avelumab, Durvalumab, a small-inhibitory RNA (siRNA), short hairpin RNA (shRNA), bifunctional RNA, antisense oligonucleotide, anti- PD-L1 antibody or functional fragment thereof, a ribozyme, a deoxyribozyme, or an aptamer.

97. The method of claim 92, further comprising administering to the subject a therapeutically effective amount of a PRDX6 inhibitor.

98. The method of claim 97, wherein the PRDX6 inhibitor is selected from: a small-inhibitory RNA (siRNA), short hairpin RNA (shRNA), bifunctional RNA, antisense oligonucleotide, anti- PRDX6 antibody or functional fragment thereof, ribozyme, deoxyribozyme, aptamer, small molecule or gene therapy that knocks out PRDX6.

99. The method of claim 92, wherein the step of determining the level of PRDX6 is performed by Northern blot analysis, Western blot analysis, quantitative or semi-quantitative reverse transcription-polymerase chain reaction (RT-PCR), ligase chain reaction (LCR), transcription- mediated amplification (TMA), strand displacement amplification (SDA), and nucleic acid sequence-based amplification (NASBA).

100. The method of claim 92, wherein the subject is a human.

101. The method of claim 92, wherein the levels of PRDX6 are determined my measuring levels of PRDX6 RNA transcripts in the test sample and / or control sample.

102. The method of claim 92, wherein the cancer is selected from: Head and neck cancer; lung cancer such as non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC); mediastinal neoplasms such as neurogenic tumors and mesenchymal tumors; gastrointestinal (GI) cancers such as esophagus, Cancers of the stomach (stomach cancer), pancreas, liver and bile ducts (including hepatocellular carcinoma (HCC)), and small and large intestine (including colorectal cancer); prostate cancer; testicular cancer; gynecological cancer, ovary Cancer; breast cancer such as breast cancer, hormone receptor positive breast cancer, Her2 positive breast cancer, and triple negative breast cancer; endocrine cancer; soft tissue sarcoma such as fibrosarcoma, rhabdomyosarcoma, angiosarcoma, Kaposi sarcoma; Osteosarcoma, myeloma, osteosarcoma, Ewing tumor, fibrosarcoma, osteochondroma, osteoblastoma, and chondroblastoma; mesothelioma; skin cancer, basal cell carcinoma, squamous cell carcinoma, Merkel Cell carcinoma and melanoma; central nervous system Neoplasms of the brain, such as astrocytoma, glioblastoma, glioma, neuroblastoma, and retinoblastoma; lymphoma and leukemia, such as B-cell non-Hodgkin lymphoma (NHL), T-cell non-Hodgkin Lymphoma, chronic B-cell lymphocytic leukemia (B- CLL), chronic T-cell lymphocytic leukemia (T-CLL), Hodgkin's disease (HD), large granularlymphocytic leukemia (LGL), chronic myeloid leukemia (CML), Acute myeloid / myelocytic leukemia (AML), acute lymphoid / lymphoblastic leukemia (ALL), multiple myeloma (MM), plasmacytoma, and myelodysplastic syndrome (MDS).

103. The method of claim 92, wherein the cancer is non-small cell lung cancer (NSCLC).

104. A method of assessing the efficacy or effectiveness of a PD1 or PD-L1 inhibitor therapy treatment being administered to a cancer subject, the method comprising: - measuring the activity level of a pharmacodynamic biomarker PRDX6 in a first sample obtained from the subject at a time t0; - administering an PD1 inhibitor and / or a PRDX6 inhibitor after said time t0; - measuring the activity level of the pharmacodynamic biomarker PRDX6 in a second sample obtained from the subject at time t1; and - wherein a decrease in the level of the pharmacodynamic biomarker PRDX6 in the second sample relative to the first sample is an indication that the PD1 treatment is or will be effective for treating cancer in the subject.

105. The method of claim 104, wherein the PD1 inhibitor is selected from: Pembrolizumab, Nivolumab, Cemiplimab, Toripalimab, Retifanlimab, Dostarlimab, a small-inhibitory RNA (siRNA), short hairpin RNA (shRNA), bifunctional RNA, antisense oligonucleotide, anti-PD1 antibody or functional fragment thereof, a ribozyme, a deoxyribozyme, or an aptamer.

106. The method of claim 104, wherein the PD-L1 inhibitor is selected from: Atezolizumab, Avelumab, Durvalumab, a small-inhibitory RNA (siRNA), short hairpin RNA (shRNA), bifunctional RNA, antisense oligonucleotide, anti- PD-L1 antibody or functional fragment thereof, a ribozyme, a deoxyribozyme, or an aptamer.

107. The method of claim 104, wherein the PRDX6 inhibitor is selected from: a small-inhibitory RNA (siRNA), short hairpin RNA (shRNA), bifunctional RNA, antisense oligonucleotide, anti- PRDX6 antibody or functional fragment thereof, ribozyme, deoxyribozyme, aptamer, small molecule or gene therapy that knocks out PRDX6.

108. The method of claim 104, wherein the cancer is selected from: Head and neck cancer; lung cancer such as non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC); mediastinal neoplasms such as neurogenic tumors and mesenchymal tumors; gastrointestinal (GI) cancers such as esophagus, Cancers of the stomach (stomach cancer), pancreas, liver and bile ducts (including hepatocellular carcinoma (HCC)), and small and large intestine (including colorectal cancer); prostate cancer; testicular cancer; gynecological cancer, ovary Cancer; breast cancer such as breast cancer, hormone receptor positive breast cancer, Her2 positive breast cancer, and triple negative breast cancer; endocrine cancer; soft tissue sarcoma such as fibrosarcoma, rhabdomyosarcoma, angiosarcoma, Kaposi sarcoma; Osteosarcoma, myeloma, osteosarcoma, Ewing tumor, fibrosarcoma, osteochondroma, osteoblastoma, and chondroblastoma; mesothelioma; skin cancer, basal cell carcinoma, squamous cell carcinoma, Merkel Cell carcinoma and melanoma; central nervous system Neoplasms of the brain, such as astrocytoma, glioblastoma, glioma, neuroblastoma, and retinoblastoma; lymphoma and leukemia, such as B-cell non-Hodgkin lymphoma (NHL), T-cell non-Hodgkin Lymphoma, chronic B-cell lymphocytic leukemia (B- CLL), chronic T-cell lymphocytic leukemia (T-CLL), Hodgkin's disease (HD), large granular lymphocytic leukemia (LGL), chronic myeloid leukemia (CML), Acute myeloid / myelocytic leukemia (AML), acute lymphoid / lymphoblastic leukemia (ALL), multiple myeloma (MM), plasmacytoma, and myelodysplastic syndrome (MDS).

109. The method of claim 104, wherein the cancer is non-small cell lung cancer (NSCLC).

110. The method of claim 104, wherein the subject is a human.

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