Biomarkers for use in cancer therapy

Abstract

Provided herein are methods of using one or more cytokines, one or more chemokines, one or more soluble cell receptors, one or more growth factors, or any combination thereof to determine whether to: (a) select a patient subject suffering from cancer for treatment with elraglusib, (b) treat a patient suffering from cancer with elraglusib, or (c) continue to treat a patient suffering from cancer and receiving treatment with elraglusib.

Description

Atny Docket No. ACTU-42816.601 BIOMARKERS FOR USE IN CANCER THERAPY RELATED APPLICATION INFORMATION

[0001] This application claims priority to U.S. Application No.63 / 560,331, filed on March 1, 2024, the contents of which are herein incorporated by reference. FIELD

[0002] Provided herein are methods for selecting, treating, and monitoring a patient sufering from cancer. In particular, the present disclosure provides methods of using one or more cytokines, one or more chemokines, one or more soluble cel receptors, one or more growth factors, or any combination thereof to determine whether to: (a) select a patient sufering from cancer for treatment with elraglusib, (b) treat a patient sufering from cancer with elraglusib, or (c) continue to treat a patient sufering from cancer and receiving treatment with elraglusib. BACKGROUND

[0003] Metastatic cancer is cancer that spreads from where it started to a distant part of the body. Metastases to critical organs often lead to functional impairments, severe complications, and a decline in overal health status. Moreover, the aggressive nature of some types of metastatic cancers contribute to its resistance to conventional treatment modalities, such as chemotherapy, targeted therapy, and immunotherapy. Despite eforts to develop novel therapeutic strategies, including combination therapies and personalized medicine approaches, the survival rates for patients with advanced metastatic cancer beyond five years post-diagnosis remains low.

[0004] In recent years, there has been growing interest in targeting specific molecular pathways implicated in metastatic cancer pathogenesis to improve treatment eficacy and patient outcomes. One such pathway of interest is the glycogen synthase kinase-3 (GSK-3) signaling pathway. GSK-3 is a multifunctional protein kinase involved in various celular processes, including cel proliferation, diferentiation, apoptosis, and metabolism. Dysregulation of GSK-3 activity has been implicated in the development and progression of various cancers, including pancreatic cancer.

[0005] Preclinical studies have demonstrated that aberant GSK-3 activity can promote tumor growth, invasion, and metastasis in pancreatic cancer cels. Consequently, GSK-3 has emergedAtny Docket No. ACTU-42816.601 as a promising therapeutic target for cancer treatment, including pancreatic cancer. Inhibitors of GSK-3 have shown eficacy in preclinical models of pancreatic cancer by inhibiting tumor cel proliferation, inducing apoptosis, and suppressing tumor angiogenesis and metastasis. Additionaly, the inclusion of predictive cancer biomarkers in these methods is of paramount importance, as they can further enhance the efficacy of GSK-3 inhibitors by aiding in the prediction of therapy outcomes, assessment of tumor response to treatment, determination of prognosis, patient stratification for initial therapies, and optimization of treatment strategies tailored to individual patients.

[0006] However, despite promising preclinical data, the clinical translation of GSK-3 inhibitors as anti-cancer agents, particularly in the context of metastatic cancers, remains a subject of ongoing research. Likewise, the lack of predictive biomarkers for patient selection and response assessment poses a significant chalenge in the successful implementation of cancer treatments in clinical practice. Without the use of predictive biomarkers, the eficacy of cancer treatment may be compromised, leading to suboptimal outcomes for patients. While there is a rationale for targeting GSK-3 in cancer therapy, the clinical efficacy and safety of GSK-3 inhibitors, either as monotherapy or in combination with standard treatments and the use of predictive cancer biomarkers, need to be further evaluated. SUMMARY

[0007] Embodiments of the present disclosure include methods of selecting, treating, and monitoring a patient sufering from cancer.

[0008] Provided herein are methods of treating a patient sufering from cancer, the method comprising the steps of: receiving information on whether a level of one or more cytokines, one or more chemokines, one or more soluble cel receptors, or one or more growth factors, or any combination thereof in a biological sample obtained from a subject sufering from cancer is higher or lower than one or more predetermined thresholds, where the one or more cytokines are IL-6, IL-8, IL-34, TRAIL, CCL3, CHI3L1, IL-1 alpha, or any combination thereof, the one or more chemokines are CCL2, CCL21, CXCL5 or any combination thereof, the one or more soluble cel receptor is CD119, TRAIL.R2, CD54, CD95, or any combination thereof, and the growth factor is VEGF and, administering elraglusib (a GSK-3 inhibitor) to the patient if:

[0009] (1) the level of one or more of the folowing chemokines is: (i) below the predetermined threshold: IL-6, IL-8, IL-34, TRAIL, CCL3, CHI3L1, IL-1 alpha, or anyAtny Docket No. ACTU-42816.601 combination thereof; (i) above the predetermined threshold: TRAIL; or (ii) any combination of (i) and (i);

[0010] (2) the level of one or more of the folowing chemokines is below the predetermined threshold: CCL2, CCL21, CXCL5 or any combination thereof;

[0011] (3) the level of one or more of the folowing soluble receptors is: (i) below the predetermined threshold: CD119, TRAIL.R2, CD54, or any combination thereof; (i) above the predetermined threshold: CD95; or (ii) any combination of (i) and (i);

[0012] (4) the level of VEGF is below the predetermined threshold; or

[0013] (5) any combination of (1)-(4); or

[0014] not administering elraglusib to the patient if:

[0015] (1) the level of one or more of the folowing chemokines is: (i) above the predetermined threshold: IL-6, IL-8, IL-34, CCL3, CHI3L1, IL-1 alpha, or any combination thereof; (i) below the predetermined threshold: TRAIL; or (ii) any combination of (i) and (i);

[0016] (2) the level of one or more of the folowing chemokines is above the predetermined threshold: CCL2, CCL21, CXCL5 or any combination thereof;

[0017] (3) the level of one or more of the folowing soluble receptors is: (i) above the predetermined threshold: CD119, TRAIL.R2, CD54, or any combination thereof; (i) below the predetermined threshold: CD95; or (ii) any combination of (i) and (i);

[0018] (4) the level of VEGF is above the predetermined threshold; or

[0019] (5) any combination of (1)-(4).

[0020] In some embodiments, the predetermined thresholds used in the method is: (a) from about 1.0 to about 25 pg / mL for IL-6; (b) from about 8.0 to about 35 pg / mL for IL-8; (c) from about 150 to about 300 pg / mL for CCL2; (d) from about 325 to about 450 pg / mL for IL-34; (e) from about 85 to about 120 pg / mL for CD119; (f) from about 525 to about 725 pg / mL for CCL21; (g) from about 55 to about 90 pg / mL for TRAIL; (h) from about 65 to about 100 pg / mL for TRAIL.R2; (i) from about 30 to about 135 pg / mL for VEGF; (j) from about 415 to about 500 pg / mL for CXCL5; (k) from about 300,000 to about 450,000 pg / mL for CD54; (l) from about 300 to about 415 pg / mL for CCL3; (m) from about 9000 to about 10,500 pg / mL for CD95; (n) from about 100,000 to about 175,000 pg / mL for CHI3L1; or (o) from about 25 to about 45 pg / mL for IL-1 alpha.Atny Docket No. ACTU-42816.601

[0021] In some embodiments, the biological sample is a liquid sample, a tumor biopsy sample, or a combination thereof.

[0022] In further embodiments, the liquid sample, is a whole blood sample, a plasma sample, a serum sample, a urine sample, or any combination thereof.

[0023] In some embodiments, the tumor biopsy sample is a brush cytology biopsy sample, or a piece of tumor tissue.

[0024] In certain embodiments, the subject is treated with a combination of elraglusib and a chemotherapeutic agent.

[0025] In further embodiments, the chemotherapeutic agent is a taxane, a combination of leucovorin calcium, fluorouracil, irinotecan, and oxaliplatin, gemcitabine, a combination of gemcitabine and taxane, or a combination of irinotecan, leucovorin and fluorouracil.

[0026] In certain embodiments, the cancer is cancer of oral cavity, salivary gland cancer, esophageal cancer, galbladder cancer, cancer of bile ducts, liver cancer, stomach cancer, pancreatic cancer, colon cancer, rectal cancer, anal cancer, gastrointestinal stromal tumors, gastrointestinal carcinoid tumors, breast cancer, cervical cancer, endometrial cancer, ovarian cancer, and vaginal cancer, bladder cancer, testicular cancer, prostate cancer, kidney cancer, renal cel carcinoma, adrenal cancer, and penile cancer, thyroid cancer, eye cancer, retinoblastoma, skin cancer, basal cel carcinoma, melanoma, neuroendocrine tumor, neuroblastoma, head and neck cancer, nasal cancer, laryngeal cancer, lung cancer, malignant mesothelioma, aplastic anemia, Non-Hodgkin's lymphoma, Hodgkin's lymphoma, acute lymphocytic (lymphoblastic) leukemia, T-cel leukemia, acute myeloid leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, multiple myeloma, myelodysplastic syndrome, hairy cel leukemia, lymphoplasmacytic lymphoma (Waldenstrom's macroglobulinemia), tumors of central nervous system (CNS), glioblastoma, glioma, astrocytoma, meduloblastoma, CNS lymphoma, and pituitary tumor, bone cancer, osteosarcoma, rhabdomyosarcoma, sarcoma, or any combination thereof. In other aspects, the cancer is pancreatic cancer, a sarcoma, non-Hodgkin lymphoma, glioma, renal cancer, breast cancer, or any combination thereof.

[0027] Provided herein are methods of selecting a patient sufering from cancer for treatment with elraglusib, the method comprising the steps of: receiving information on whether a level of one or more cytokines, one or more chemokines, one or more soluble cel receptors, or one orAtny Docket No. ACTU-42816.601 more growth factors, or any combination thereof in a biological sample obtained from a patient sufering from cancer is higher or lower than one or more predetermined thresholds, where the one or more cytokines are IL-6, IL-8, IL-34, TRAIL, CCL3, CHI3L1, IL-1 alpha, or any combination thereof, the one or more chemokines are CCL2, CCL21, CXCL5 or any combination thereof, the one or more soluble cel receptor is CD119, TRAIL.R2, CD54, CD95, or any combination thereof, and the growth factor is VEGF and, selecting a patient for treatment with elraglusib if:

[0028] (1) the level of one or more of the folowing chemokines is: (i) below the predetermined threshold: IL-6, IL-8, IL-34, TRAIL, CCL3, CHI3L1, IL-1 alpha, or any combination thereof; (i) above the predetermined threshold: TRAIL; or (ii) any combination of (i) and (i);

[0029] (2) the level of one or more of the folowing chemokines is below the predetermined threshold: CCL2, CCL21, CXCL5 or any combination thereof;

[0030] (3) the level of one or more of the folowing soluble receptors is: (i) below the predetermined threshold: CD119, TRAIL.R2, CD54, or any combination thereof; (i) above the predetermined threshold: CD95; or (ii) any combination of (i) and (i);

[0031] (4) the level of VEGF is below the predetermined threshold; or

[0032] (5) any combination of (1)-(4); or

[0033] not selecting a patient for treatment with elraglusib if:

[0034] (1) the level of one or more of the folowing chemokines is: (i) above the predetermined threshold: IL-6, IL-8, IL-34, CCL3, CHI3L1, IL-1 alpha, or any combination thereof; (i) below the predetermined threshold: TRAIL; or (ii) any combination of (i) and (i);

[0035] (2) the level of one or more of the folowing chemokines is above the predetermined threshold: CCL2, CCL21, CXCL5 or any combination thereof;

[0036] (3) the level of one or more of the folowing soluble receptors is: (i) above the predetermined threshold: CD119, TRAIL.R2, CD54, or any combination thereof; (i) below the predetermined threshold: CD95; or (ii) any combination of (i) and (i);

[0037] (4) the level of VEGF is above the predetermined threshold; or

[0038] (5) any combination of (1)-(4).

[0039] In some embodiments, the predetermined thresholds used in the method is: (a) from about 1.0 to about 25 pg / mL for IL-6; (b) from about 8.0 to about 35 pg / mL for IL-8; (c) fromAtny Docket No. ACTU-42816.601 about 150 to about 300 pg / mL for CCL2; (d) from about 325 to about 450 pg / mL for IL-34; (e) from about 85 to about 120 pg / mL for CD119; (f) from about 525 to about 725 pg / mL for CCL21; (g) from about 55 to about 90 pg / mL for TRAIL; (h) from about 65 to about 100 pg / mL for TRAIL.R2; (i) from about 30 to about 135 pg / mL for VEGF; (j) from about 415 to about 500 pg / mL for CXCL5; (k) from about 300,000 to about 450,000 pg / mL for CD54; (l) from about 300 to about 415 pg / mL for CCL3; (m) from about 9000 to about 10,500 pg / mL for CD95; (n) from about 100,000 to about 175,000 pg / mL for CHI3L1; or (o) from about 25 to about 45 pg / mL for IL-1 alpha.

[0040] In some embodiments, the biological sample is a liquid sample, a tumor biopsy sample, or a combination thereof.

[0041] In further embodiments, the liquid sample, is a whole blood sample, a plasma sample, a serum sample, a urine sample, or any combination thereof.

[0042] In some embodiments, the tumor biopsy sample is a brush cytology biopsy sample, or a piece of tumor tissue.

[0043] In certain embodiments, the subject is treated with a combination of elraglusib and a chemotherapeutic agent.

[0044] In further embodiments, the chemotherapeutic agent is a taxane, a combination of leucovorin calcium, fluorouracil, irinotecan, and oxaliplatin, gemcitabine, a combination of gemcitabine and taxane, or a combination of irinotecan, leucovorin and fluorouracil.

[0045] In certain embodiments, the cancer is cancer of oral cavity, salivary gland cancer, esophageal cancer, galbladder cancer, cancer of bile ducts, liver cancer, stomach cancer, pancreatic cancer, colon cancer, rectal cancer, anal cancer, gastrointestinal stromal tumors, gastrointestinal carcinoid tumors, breast cancer, cervical cancer, endometrial cancer, ovarian cancer, and vaginal cancer, bladder cancer, testicular cancer, prostate cancer, kidney cancer, renal cel carcinoma, adrenal cancer, and penile cancer, thyroid cancer, eye cancer, retinoblastoma, skin cancer, basal cel carcinoma, melanoma, neuroendocrine tumor, neuroblastoma, head and neck cancer, nasal cancer, laryngeal cancer, lung cancer, malignant mesothelioma, aplastic anemia, Non-Hodgkin's lymphoma, Hodgkin's lymphoma, acute lymphocytic (lymphoblastic) leukemia, T-cel leukemia, acute myeloid leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, multiple myeloma, myelodysplastic syndrome, hairy cel leukemia, lymphoplasmacytic lymphoma (Waldenstrom'sAtny Docket No. ACTU-42816.601 macroglobulinemia), tumors of central nervous system (CNS), glioblastoma, glioma, astrocytoma, meduloblastoma, CNS lymphoma, and pituitary tumor, bone cancer, osteosarcoma, rhabdomyosarcoma, sarcoma, or any combination thereof. In other aspects, the cancer is pancreatic cancer, a sarcoma, non-Hodgkin lymphoma, glioma, renal cancer, breast cancer, or any combination thereof.

[0046] Provided herein are methods of monitoring a patient sufering from cancer and receiving treatment with elraglusib the method comprising the steps of: receiving information on whether a level of one or more cytokines, one or more chemokines, one or more soluble cel receptors, or one or more growth factors, or any combination thereof in a biological sample obtained from a patient sufering from cancer and receiving treatment with elraglusib is higher or lower than one or more predetermined thresholds, where the one or more cytokines are IL-6, IL- 8, IL-34, TRAIL, CCL3, CHI3L1, IL-1 alpha, or any combination thereof, the one or more chemokines are CCL2, CCL21, CXCL5 or any combination thereof, the one or more soluble cel receptor is CD119, TRAIL.R2, CD54, CD95, or any combination thereof, and the growth factor is VEGF and, continuing to treat the patient with elraglusib if:

[0047] (1) the level of one or more of the folowing chemokines is: (i) below the predetermined threshold: IL-6, IL-8, IL-34, TRAIL, CCL3, CHI3L1, IL-1 alpha, or any combination thereof; (i) above the predetermined threshold: TRAIL; or (ii) any combination of (i) and (i);

[0048] (2) the level of one or more of the folowing chemokines is below the predetermined threshold: CCL2, CCL21, CXCL5 or any combination thereof;

[0049] (3) the level of one or more of the folowing soluble receptors is: (i) below the predetermined threshold: CD119, TRAIL.R2, CD54, or any combination thereof; (i) above the predetermined threshold: CD95; or (ii) any combination of (i) and (i);

[0050] (4) the level of VEGF is below the predetermined threshold; or

[0051] (5) any combination of (1)-(4); or

[0052] discontinuing to treat the patient with elraglusib if:

[0053] (1) the level of one or more of the folowing chemokines is: (i) above the predetermined threshold: IL-6, IL-8, IL-34, CCL3, CHI3L1, IL-1 alpha, or any combination thereof; (i) below the predetermined threshold: TRAIL; or (ii) any combination of (i) and (i);Atny Docket No. ACTU-42816.601

[0054] (2) the level of one or more of the folowing chemokines is above the predetermined threshold: CCL2, CCL21, CXCL5 or any combination thereof;

[0055] (3) the level of one or more of the folowing soluble receptors is: (i) above the predetermined threshold: CD119, TRAIL.R2, CD54, or any combination thereof; (i) below the predetermined threshold: CD95; or (ii) any combination of (i) and (i);

[0056] (4) the level of VEGF is above the predetermined threshold; or

[0057] (5) any combination of (1)-(4).

[0058] In some embodiments, the predetermined thresholds used in the method is: (a) from about 1.0 to about 25 pg / mL for IL-6; (b) from about 8.0 to about 35 pg / mL for IL-8; (c) from about 150 to about 300 pg / mL for CCL2; (d) from about 325 to about 450 pg / mL for IL-34; (e) from about 85 to about 120 pg / mL for CD119; (f) from about 525 to about 725 pg / mL for CCL21; (g) from about 55 to about 90 pg / mL for TRAIL; (h) from about 65 to about 100 pg / mL for TRAIL.R2; (i) from about 30 to about 135 pg / mL for VEGF; (j) from about 415 to about 500 pg / mL for CXCL5; (k) from about 300,000 to about 450,000 pg / mL for CD54; (l) from about 300 to about 415 pg / mL for CCL3; (m) from about 9000 to about 10,500 pg / mL for CD95; (n) from about 100,000 to about 175,000 pg / mL for CHI3L1; or (o) from about 25 to about 45 pg / mL for IL-1 alpha.

[0059] In some embodiments, the biological sample is a liquid sample, a tumor biopsy sample, or a combination thereof.

[0060] In further embodiments, the liquid sample, is a whole blood sample, a plasma sample, a serum sample, a urine sample, or any combination thereof.

[0061] In some embodiments, the tumor biopsy sample is a brush cytology biopsy sample, or a piece of tumor tissue.

[0062] In certain embodiments, the subject is treated with a combination of elraglusib and a chemotherapeutic agent.

[0063] In further embodiments, the chemotherapeutic agent is a taxane, a combination of leucovorin calcium, fluorouracil, irinotecan, and oxaliplatin, gemcitabine, a combination of gemcitabine and taxane, or a combination of irinotecan, leucovorin and fluorouracil.

[0064] In certain embodiments, the cancer is cancer of oral cavity, salivary gland cancer, esophageal cancer, galbladder cancer, cancer of bile ducts, liver cancer, stomach cancer, pancreatic cancer, colon cancer, rectal cancer, anal cancer, gastrointestinal stromal tumors,Atny Docket No. ACTU-42816.601 gastrointestinal carcinoid tumors, breast cancer, cervical cancer, endometrial cancer, ovarian cancer, and vaginal cancer, bladder cancer, testicular cancer, prostate cancer, kidney cancer, renal cel carcinoma, adrenal cancer, and penile cancer, thyroid cancer, eye cancer, retinoblastoma, skin cancer, basal cel carcinoma, melanoma, neuroendocrine tumor, neuroblastoma, head and neck cancer, nasal cancer, laryngeal cancer, lung cancer, malignant mesothelioma, aplastic anemia, Non-Hodgkin's lymphoma, Hodgkin's lymphoma, acute lymphocytic (lymphoblastic) leukemia, T-cel leukemia, acute myeloid leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, multiple myeloma, myelodysplastic syndrome, hairy cel leukemia, lymphoplasmacytic lymphoma (Waldenstrom's macroglobulinemia), tumors of central nervous system (CNS), glioblastoma, glioma, astrocytoma, meduloblastoma, CNS lymphoma, and pituitary tumor, bone cancer, osteosarcoma, rhabdomyosarcoma, sarcoma, or any combination thereof. In other aspects, the cancer is pancreatic cancer, a sarcoma, non-Hodgkin lymphoma, glioma, renal cancer, breast cancer, or any combination thereof. DETAILED DESCRIPTION

[0065] Provided herein are methods for selecting, treating, and monitoring a patient sufering from cancer. In particular, the present disclosure provides methods of using one or more cytokines, one or more chemokines, one or more soluble cel receptors, one or more growth factors, or any combination thereof to determine whether to: (a) select a patient sufering from cancer for treatment with elraglusib, (b) treat a patient sufering from cancer with elraglusib, or (c) continue to treat a patient sufering from cancer and receiving treatment with elraglusib. DEFINITIONS

[0066] The terms "comprise(s)," "include(s)," "having," "has," "can," "contain(s)," and variants thereof, as used herein, are intended to be open-ended transitional phrases, terms, or words that do not preclude the possibility of additional acts or structures. The singular forms "a," "and," and "the" include plural references unless the context clearly dictates otherwise. The present disclosure also contemplates other embodiments "comprising," "consisting of," and "consisting essentialy of," the embodiments or elements presented herein, whether explicitly set forth or not.Atny Docket No. ACTU-42816.601

[0067] For the recitation of numeric ranges herein, each intervening number there between with the same degree of precision is explicitly contemplated. For example, for the range of 69, the numbers 7 and 8 are contemplated in addition to 6 and 9, and for the range 6.0-7.0, the number 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, and 7.0 are explicitly contemplated. Unless otherwise defined herein, scientific, and technical terms used in connection with the present disclosure shal have the meanings that are commonly understood by those of ordinary skil in the art. The meaning and scope of the terms should be clear; in the event, however of any latent ambiguity, definitions provided herein take precedent over any dictionary or extrinsic definition. Further, unless otherwise required by context, singular terms shal include pluralities and plural terms shal include the singular.

[0068] As used herein in the specification and in the claims, “or” should be understood to have the same meaning as “and / or” as defined above. For example, when separating items in a list, “or” or “and / or” shal be interpreted as being inclusive, e.g., the inclusion of at least one, but also including more than one, of a number or list of elements, and, optionaly, additional unlisted items. Only terms clearly indicated to the contrary, such as “only one of” or “exactly one of” or, when used in the claims, “consisting of,” wil refer to the inclusion of exactly one element of a number or list of elements. In general, the term “or” as used herein shal only be interpreted as indicating exclusive alternatives (e.g., “one or the other but not both”) when preceded by terms of exclusivity, such as “either,” “one of” “only one of” or “exactly one of.”

[0069] As used herein, the term "administering" means either directly administering a compound or composition of the present invention, or administering a prodrug, derivative or analog which wil form an equivalent amount of the active compound or substance within the body.

[0070] As used herein, the term “combination” is used in its broadest sense and means that a subject or patient is administered at least two agents, more particularly elraglusib and at least one other therapeutic agent. More particularly, the term “in combination” refers to the concomitant administration of two (or more) active agents for the treatment of a, e.g., single disease state. As used herein, the active agents may be combined and administered in a single dosage form, may be administered as separate dosage forms at the same time, or may be administered as separate dosage forms that are administered alternately or sequentialy on the same or separate days. In one embodiment of the presently disclosed subject mater, the active agents are combined andAtny Docket No. ACTU-42816.601 administered in a single dosage form. In another embodiment, the active agents are administered in separate dosage forms (e.g., wherein it is desirable to vary the amount of one but not the other). The single dosage form may include additional active agents for the treatment of the disease state.

[0071] As used herein, the term “chemokine” or “chemotactic cytokines” as used interchangeable herein, refer to a large family of smal, secreted proteins that signal through cel surface G protein-coupled heptahelical chemokine receptors. Chemokines are known for their ability to stimulate the migration of cels, most notably, white blood cels (e.g., leukocytes). Examples of chemokines are monocyte chemoatractant protein-1 (MCP-1 / CCL2), CC motif chemokine ligand 21 (CCL21), C-X-X Motif Chemokine Ligand 5 (CXCL5), or any combination thereof.

[0072] As used herein, the term “cytokine” refers to secreted proteins released by cels that have a specific efect on the interactions and communications between cels. The term “cytokine” is a general name and other names include lymphokine (cytokines made by lymphocytes), monokine (cytokines made by monocytes), chemokine (cytokines with chemotactic activities), and interleukin (cytokines made by one leukocyte and acting on other leukocytes). Cytokines may act on the cels that secrete them (autocrine action), on nearby cels (paracrine action), or in some instances on distant cels (endocrine action). There are both pro- inflammatory cytokines and anti-inflammatory cytokines. Examples of cytokines include interleukin-6 (IL-6), interleukin-8 (IL-8), interleukin-34 (IL-34), tumor necrosis factor related apoptosis-inducing ligand (TRAIL), macrophage inflammatory protein alpha (MIP-1α / CCL3), chitinase-3 like protein-1 (CHI3L1), interleukin-1 alpha (IL-1α), or any combination thereof.

[0073] As used herein, the term “elraglusib” or “9-ING-41” as used interchangeably herein, refers to a Glycogen Synthase Kinase-3 (GSK-3) inhibitor having the chemical name 3-(5- Fluoro-benzofuran-3-yl)-4-(5-methyl-5H-[1,3]dioxolo[4,5f]indol-7-yl)-pyrrole-2,5-dione and the molecular formula C22H13N2O5F. The chemical structure of elraglusib is shown below in Formula I.Atny Docket No. ACTU-42816.601

[0074] As used biologicaly active molecule (e.g., DNA, RNA, protein and / or peptide) that can afect the growth of cels. An example of a growth factor is vascular endothelial growth factor (VEGF).

[0075] As used herein, the terms “patient” or “subject” refer to organisms to be subject to various tests provided by the technology. The term “subject” includes animals, preferably mammals, including humans. In a prefered embodiment, the subject is a primate. In an even more prefered embodiment, the subject is a human. Further with respect to diagnostic methods, a prefered subject is a vertebrate subject. A prefered vertebrate is warm-blooded; a prefered warm-blooded vertebrate is a mammal. A prefered mammal is most preferably a human. As used herein, the term “subject' includes both human and animal subjects. Thus, veterinary therapeutic uses are provided herein. As such, the present technology provides for the diagnosis of mammals such as humans, as wel as those mammals of importance due to being endangered, such as Siberian tigers; of economic importance, such as animals raised on farms for consumption by humans; and / or animals of social importance to humans, such as animals kept as pets or in zoos. Examples of such animals include but are not limited to: carnivores such as cats and dogs; swine, including pigs, hogs, and wild boars; ruminants and / or ungulates such as catle, oxen, sheep, girafes, deer, goats, bison, and camels; pinnipeds; and horses. Thus, also provided is the diagnosis and treatment of livestock, including, but not limited to, domesticated swine, ruminants, ungulates, horses (including race horses), and the like.

[0076] As used herein, whether by itself or in conjunction with another term or terms, it should be understood that the phrases "method of treating" and "method of treatment" may be used interchangeably with the phrase "for use in the treatment of a particular disease”.

[0077] As used herein, the term “predetermined threshold(s)” refers to a cutof or cutpoint value that is used to assess diagnostic, prognostic, or therapeutic efficacy and that has beenAtny Docket No. ACTU-42816.601 linked or is associated herein with various clinical parameters (e.g., presence of disease, stage of disease, severity of disease, progression, non-progression, or improvement of disease, etc.). In some aspects, the predetermined threshold has been linked or is associated with one or more types of cancer (e.g., pancreatic cancer, a sarcoma, non-Hodgkin lymphoma, glioma, renal cancer, or breast cancer). Suitable predetermined threshold amounts can be determined from a reference sample to be analyzed together, i.e. simultaneously or subsequently, with the biological sample obtained from the subject or patient of interest (e.g., a subject or patient sufering from cancer). This disclosure provides exemplary predetermined thresholds for one or more cytokines, one or more chemokines, one or more soluble receptors, or one or more growth factors for use in the methods described herein.

[0078] As used herein, whether used alone or in conjunction with another term or terms, "therapeutic" and "therapeuticaly efective amount" refer to an amount of a compound or composition that (a) treats a particular condition, symptom, disorder, or disease described herein; (b) atenuates, ameliorates, or eliminates one or more symptoms of a particular condition, disorder, or disease described herein; (c) delays the onset or relapse (reoccurence) of a particular condition, symptom, disorder, or disease described herein; (d) prevents the onset of a particular condition, symptom, disorder, or disease described herein. It should be understood that the terms "therapeutic" and "therapeuticaly efective" encompass any one of the aforementioned efects (a)-(d), either alone or in combination with any of the others (a)-(d).

[0079] As used herein, the term “sample” is used in its broadest sense. In one sense, it is meant to include a specimen obtained from any source, including biological samples. Biological samples may be obtained from animals (including humans) and encompass fluids, solids, tissues, and gases. Such examples are not however to be construed as limiting the sample types. As used herein, “sample” and “biological sample” are used interchangeably.

[0080] In some aspects, a sample is a fluid sample such as a liquid sample. Examples of liquid samples that may be assayed include bodily fluids (e.g., whole blood, serum, plasma, saliva, urine, ocular fluid, semen, sputum, sweat, tears, and spinal fluid), samples from water sources or sewage samples; and food samples. Viscous liquid, semisolid, or solid specimens may be used to create liquid solutions, eluates, suspensions, or extracts that can be samples. For example, throat or genital swabs may be suspended in a liquid solution to make a sample. InAtny Docket No. ACTU-42816.601 other aspects, the biological sample is a tumor biopsy sample, such as, a brush cytology biopsy sample, a piece of tumor tissue or combinations thereof.

[0081] Samples can include a combination of liquids, solids (e.g., tissues), or any combination thereof (e.g., a suspension of lysed or unlysed cels in a bufer or solution). Samples can comprise biological materials, such as cels, microbes, organeles, and biochemical complexes. Liquid samples can be made from solid, semisolid, or highly viscous materials, such as fecal mater, tissues, organs, biological fluids, or other samples that are not fluid in nature. For example, solid or semisolid samples can be mixed with an appropriate solution, such as a bufer, a diluent, and / or extraction bufer. The sample can be macerated, frozen and thawed, or otherwise extracted to form a fluid sample. Residual particulates may be removed or reduced using conventional methods, such as filtration or centrifugation.

[0082] A variety of cel types, tissue, or bodily fluid may be utilized to obtain a sample or biological sample. Such cel types, tissues, and fluid may include sections of tissues such as biopsy and autopsy samples, oropharyngeal specimens, nasopharyngeal specimens, nasal mucus specimens, frozen sections taken for histologic purposes, blood (such as whole blood, dried blood spots, etc.), plasma, serum, red blood cels, platelets, an anal sample (such as an anal swab specimen), interstitial fluid, cerebrospinal fluid, etc. Cel types and tissues may also include lymph fluid, cerebrospinal fluid, or any fluid colected by aspiration. A tissue or cel type (such as a tumor biopsy sample) may be provided by removing a sample of cels from a human and a non-human animal, but can also be accomplished by using previously isolated cels (e.g., isolated by another person, at another time, and / or for another purpose). Archival tissues, such as those having treatment or outcome history, may also be used.

[0083] As used herein, a “soluble receptor” as used herein refers to the extracelular portion of a membrane-bound receptor that retains the ability to bind to one or more ligands (e.g., proteins). Examples of soluble receptors include interferon gamma receptor 1 (CD119), tumor necrosis factor related apoptosis-inducing ligand receptor 2 (TRAIL.R2), intercelular adhesion molecule- 1 (ICAM-1 / CD54), cluster of diferentiation 95 (CD95), or any combination thereof.

[0084] As used herein, whether by themselves or in conjunction with another term or terms, "treats," "treating," "treated," and "treatment," refer to and include ameliorative, paliative, and / or curative uses and results, or any combination thereof. In other embodiments, the methods described herein can be used prophylacticaly, that is, preventatively. It should beAtny Docket No. ACTU-42816.601 understood that "prophylaxis" or a prophylactic use or result do not refer to nor require absolute or total prevention (i.e., a 100% preventative or protective use or result). As used herein, prophylaxis or a prophylactic (preventative) use or result refers to uses and results in which administration of a compound or composition diminishes or reduces the severity of a particular condition, symptom, disorder, or disease described herein; diminishes or reduces the likelihood of experiencing a particular condition, symptom, disorder, or disease described herein; or delays the onset or relapse (reoccurrence) of a particular condition, symptom, disorder, or disease described herein; or any combination of the foregoing. Methods of Treating a Patient Sufering from Cancer

[0085] Provided herein are methods of treating a patient sufering from cancer. The first step of the method involves receiving information on whether a level of one or more cytokines, one or more chemokines, one or more soluble cel receptors, or one or more growth factors, or any combination thereof in a biological sample obtained from a patient sufering from cancer is higher or lower than one or more predetermined thresholds (to its coresponding one or more cytokines, one or more chemokines, one or more soluble cel receptors, one or more growth factors, or any combination thereof). The one or more cytokines used in the method are IL-6, IL- 8, IL-34, TRAIL, CCL3, CHI3L1, IL-1 alpha, or any combination thereof. The one or more chemokines used in the method are CCL2, CCL21, CXCL5 or any combination thereof. The one or more soluble cel receptors used in the method are CD119, TRAIL.R2, CD54, CD95, or any combination thereof. The one or more growth factors used in the method if VEGF.

[0086] In some embodiments, the level (or amount) of one or more cytokines, one or more chemokines, one or more soluble cel receptors, growth factors, or any combination thereof, that is received can be determined using routine techniques known in the art. For example, the level (or amount) of one or more cytokines, on or more chemokines, one or more soluble receptors, growth factors, or any combination thereof can be determined by performing one or more of an immunoassay (e.g., such as a Luminex Immunoassay), a single molecule detection assay, protein immunoprecipitation, immunoelectrophoresis, chemical analysis, SDS-PAGE and Western blot analysis, or protein immunostaining, electrophoresis analysis, a protein assay, a competitive binding assay, a functional protein assay, a Meso Scale Discovery (MSD) immunoassay or chromatography or spectrometry methods, such as high-performance liquid chromatography (HPLC) or liquid chromatography-mass spectrometry (LC / MS) on the biological sampleAtny Docket No. ACTU-42816.601 obtained from the patient. The level (or amount) of one or more cytokines, one or more chemokines, one or more soluble cel receptors, growth factors, or any combination thereof to be determined using these techniques can be done simultaneously or sequentialy and in any order.

[0087] Once the level (or amount) of one or more cytokines, one or more chemokines, one or more soluble cel receptors, growth factors, or any combination thereof in a biological sample from a patient sufering from cancer is obtained, the level of each cytokine, chemokine, soluble cel receptor and / or growth factor is compared to a predetermined threshold to determine whether the level (or amount) of said cytokine, chemokine, soluble cel receptor and / or growth factor is above or below the predetermined threshold.

[0088] Once the level (or amount) of a cytokine, chemokine, soluble cel receptor and / or growth factor is determined to be above or below the predetermined threshold, a further determination is made of whether to administer a therapeuticaly efective amount of elraglusib to the patient. Specificaly, the patient is administered elraglusib if:

[0089] (1) the level of one or more of the folowing chemokines is: (i) below the predetermined threshold: IL-6, IL-8, IL-34, TRAIL, CCL3, CHI3L1, IL-1 alpha, or any combination thereof; (i) above the predetermined threshold: TRAIL; or (ii) any combination of (i) and (i);

[0090] (2) the level of one or more of the folowing chemokines is below the predetermined threshold: CCL2, CCL21, CXCL5 or any combination thereof;

[0091] (3) the level of one or more of the folowing soluble receptors is: (i) below the predetermined threshold: CD119, TRAIL.R2, CD54, or any combination thereof; (i) above the predetermined threshold: CD95; or (ii) any combination of (i) and (i);

[0092] (4) the level of VEGF is below the predetermined threshold; or

[0093] (5) any combination of (1)-(4).

[0094] The patient is not administered elraglusib if:

[0095] (1) the level of one or more of the folowing chemokines is: (i) above the predetermined threshold: IL-6, IL-8, IL-34, CCL3, CHI3L1, IL-1 alpha, or any combination thereof; (i) below the predetermined threshold: TRAIL; or (ii) any combination of (i) and (i);

[0096] (2) the level of one or more of the folowing chemokines is above the predetermined threshold: CCL2, CCL21, CXCL5 or any combination thereof;Atny Docket No. ACTU-42816.601

[0097] (3) the level of one or more of the folowing soluble receptors is: (i) above the predetermined threshold: CD119, TRAIL.R2, CD54, or any combination thereof; (i) below the predetermined threshold: CD95; or (ii) any combination of (i) and (i);

[0098] (4) the level of VEGF is above the predetermined threshold; or

[0099] (5) any combination of (1)-(4).

[0100] In some embodiments, the predetermined thresholds used in the above method is: (a) from about 1.0 to about 25 pg / mL for IL-6; (b) from about 8.0 to about 35 pg / mL for IL-8; (c) from about 150 to about 300 pg / mL for CCL2; (d) from about 325 to about 450 pg / mL for IL-34; (e) from about 85 to about 120 pg / mL for CD119; (f) from about 525 to about 725 pg / mL for CCL21; (g) from about 55 to about 90 pg / mL for TRAIL; (h) from about 65 to about 100 pg / mL for TRAIL.R2; (i) from about 30 to about 135 pg / mL for VEGF; (j) from about 415 to about 500 pg / mL for CXCL5; (k) from about 300,000 to about 450,000 pg / mL for CD54; (l) from about 300 to about 415 pg / mL for CCL3; (m) from about 9000 to about 10,500 pg / mL for CD95; (n) from about 100,000 to about 175,000 pg / mL for CHI3L1; or (o) from about 25 to about 45 pg / mL for IL-1 alpha.

[0101] In stil other embodiments, the predetermined thresholds used in the method is: (a) from about 1.0 to about 15 pg / mL for IL-6; (b) from about 10 to about 25 pg / mL for IL-8; (c) from about 175 to about 250 pg / mL for CCL2; (d) from about 350 to about 400 pg / mL for IL-34; (e) from about 85 to about 100 pg / mL for CD119; (f) from about 550 to about 650 pg / mL for CCL21; (g) from about 60 to about 85 pg / mL for TRAIL; (h) from about 70 to about 90 pg / mL for TRAIL.R2; (i) from about 30 to about 125 pg / mL for VEGF; (j) from about 425 to about 485 pg / mL for CXCL5; (k) from about 350,000 to about 425,000 pg / mL for CD54; (l) from about 325 to about 400 pg / mL for CCL3; (m) from about 9400 to about 10,000 pg / mL for CD95; (n) from about 125,000 to about 175,000 pg / mL for CHI3L1; or (o) from about 25 to about 40 pg / mL for IL-1 alpha.

[0102] In some embodiments, if pursuant to the above method, a determination is made using that the patient should be administered elraglusib, the patient can be administered elraglusib in an amount of about 0.5 mg / kg, about 1 mg / kg, about 2 mg / kg, about 3 mg / kg, about 4 mg / kg, about 5 mg / kg, about 6 mg / kg, about 7 mg / kg, about 8 mg / kg, about 10 mg / kg, about 11 mg / kg, about 12 mg / kg, about 13 mg / kg, about 15 mg / kg, about 16 mg / kg, about 17 mg / kg, about 18 mg / kg, about 19 mg / kg, about 20 mg / kg, about 21 mg / kg, about 22 mg / kg, about 23 mg / kg,Atny Docket No. ACTU-42816.601 about 24 mg / kg, about 25 mg / kg, about 26 mg / kg, about 27 mg / kg, about 28 mg / kg, about 29 mg / kg, about 30 mg / kg, about 31 mg / kg, about 32 mg / kg, about 33 mg / kg, about 34 mg / kg, about 35 mg / kg, about 36 mg / kg, about 37 mg / kg, about 38 mg / kg, about 39 mg / kg, about 40 mg / kg, about 41 mg / kg, about 42 mg / kg, about 43 mg / kg, about 44 mg / kg about 45 mg / kg, about 46 mg / kg, about 47 mg / kg, about 48 mg / kg, about 49 mg / kg or about 50 mg / kg, once, twice or three times per week (e.g., 7 days).

[0103] In some embodiments, the biological sample in the above is a liquid sample, a tumor biopsy sample, or a combination thereof.

[0104] In further embodiments, the liquid sample, is a whole blood sample, a plasma sample, a serum sample, a urine sample, or any combination thereof.

[0105] In some embodiments, the tumor biopsy sample is a brush cytology biopsy sample, or a piece of tumor tissue.

[0106] In certain embodiments, the patient is treated with a combination of elraglusib and a chemotherapeutic agent. In further embodiments, the chemotherapeutic agent is a taxane, a combination of leucovorin calcium, fluorouracil, irinotecan, and oxaliplatin, gemcitabine, a combination of gemcitabine and taxane, or a combination of irinotecan, leucovorin and fluorouracil.

[0107] In certain embodiments, the cancer is cancer of oral cavity, salivary gland cancer, esophageal cancer, galbladder cancer, cancer of bile ducts, liver cancer, stomach cancer, pancreatic cancer, colon cancer, rectal cancer, anal cancer, gastrointestinal stromal tumors, gastrointestinal carcinoid tumors, breast cancer, cervical cancer, endometrial cancer, ovarian cancer, and vaginal cancer, bladder cancer, testicular cancer, prostate cancer, kidney cancer, renal cel carcinoma, adrenal cancer, and penile cancer, thyroid cancer, eye cancer, retinoblastoma, skin cancer, basal cel carcinoma, melanoma, neuroendocrine tumor, neuroblastoma, head and neck cancer, nasal cancer, laryngeal cancer, lung cancer, malignant mesothelioma, aplastic anemia, Non-Hodgkin's lymphoma, Hodgkin's lymphoma, acute lymphocytic (lymphoblastic) leukemia, T-cel leukemia, acute myeloid leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, multiple myeloma, myelodysplastic syndrome, hairy cel leukemia, lymphoplasmacytic lymphoma (Waldenstrom's macroglobulinemia), tumors of central nervous system (CNS), glioblastoma, glioma, astrocytoma, meduloblastoma, CNS lymphoma, and pituitary tumor, bone cancer, osteosarcoma,Atny Docket No. ACTU-42816.601 rhabdomyosarcoma, sarcoma, or any combination thereof. In other aspects, the cancer is pancreatic cancer, a sarcoma, non-Hodgkin lymphoma, glioma, renal cancer, breast cancer, or any combination thereof. In stil some further aspects, the pancreatic cancer is metastatic pancreatic ductal adenocarcinoma (mPDAC). Methods of Selecting a Patient Sufering from Cancer

[0108] Also provided herein are methods of selecting a patient sufering from cancer for treatment with elraglusib. The first step of the method involves receiving information on whether a level of one or more cytokines, one or more chemokines, one or more soluble cel receptors, or one or more growth factors, or any combination thereof in a biological sample obtained from a patient sufering from cancer is higher or lower than one or more predetermined thresholds (to its coresponding one or more cytokines, one or more chemokines, one or more soluble cel receptors, one or more growth factors, or any combination thereof). The one or more cytokines used in the method are IL-6, IL-8, IL-34, TRAIL, CCL3, CHI3L1, IL-1 alpha, or any combination thereof. The one or more chemokines used in the method are CCL2, CCL21, CXCL5 or any combination thereof. The one or more soluble cel receptors used in the method are CD119, TRAIL.R2, CD54, CD95, or any combination thereof. The one or more growth factors used in the method if VEGF.

[0109] In some embodiments, the level (or amount) of one or more cytokines, one or more chemokines, one or more soluble cel receptors, growth factors, or any combination thereof, that is received can be determined using routine techniques known in the art. For example, the level (or amount) of one or more cytokines, on or more chemokines, one or more soluble receptors, growth factors, or any combination thereof can be determined by performing one or more of an immunoassay (e.g., such as a Luminex Immunoassay), a single molecule detection assay, protein immunoprecipitation, immunoelectrophoresis, chemical analysis, SDS-PAGE and Western blot analysis, or protein immunostaining, electrophoresis analysis, a protein assay, a competitive binding assay, a functional protein assay, a Meso Scale Discovery (MSD) immunoassay or chromatography or spectrometry methods, such as high-performance liquid chromatography (HPLC) or liquid chromatography-mass spectrometry (LC / MS) on the biological sample obtained from the patient. The level (or amount) of one or more cytokines, one or more chemokines, one or more soluble cel receptors, growth factors, or any combination thereof to be determined using these techniques can be done simultaneously or sequentialy and in any order.Atny Docket No. ACTU-42816.601

[0110] Once the level (or amount) of one or more cytokines, one or more chemokines, one or more soluble cel receptors, growth factors, or any combination thereof in a biological sample from a patient sufering from cancer is obtained, the level of each cytokine, chemokine, soluble cel receptor and / or growth factor is compared to a predetermined threshold to determine whether the level (or amount) of said cytokine, chemokine, soluble cel receptor and / or growth factor is above or below the predetermined threshold.

[0111] Once the level (or amount) of a cytokine, chemokine, soluble cel receptor and / or growth factor is determined to be above or below the predetermined threshold, a further determination is made of whether to select a patient for treatment with elraglusib. Specificaly, the patient is selected for treatment with elraglusib if:

[0112] (1) the level of one or more of the folowing chemokines is: (i) below the predetermined threshold: IL-6, IL-8, IL-34, TRAIL, CCL3, CHI3L1, IL-1 alpha, or any combination thereof; (i) above the predetermined threshold: TRAIL; or (ii) any combination of (i) and (i);

[0113] (2) the level of one or more of the folowing chemokines is below the predetermined threshold: CCL2, CCL21, CXCL5 or any combination thereof;

[0114] (3) the level of one or more of the folowing soluble receptors is: (i) below the predetermined threshold: CD119, TRAIL.R2, CD54, or any combination thereof; (i) above the predetermined threshold: CD95; or (ii) any combination of (i) and (i);

[0115] (4) the level of VEGF is below the predetermined threshold; or

[0116] (5) any combination of (1)-(4).

[0117] In contrast, the patient is not selected for treatment with elraglusib if:

[0118] (1) the level of one or more of the folowing chemokines is: (i) above the predetermined threshold: IL-6, IL-8, IL-34, CCL3, CHI3L1, IL-1 alpha, or any combination thereof; (i) below the predetermined threshold: TRAIL; or (ii) any combination of (i) and (i);

[0119] (2) the level of one or more of the folowing chemokines is above the predetermined threshold: CCL2, CCL21, CXCL5 or any combination thereof;

[0120] (3) the level of one or more of the folowing soluble receptors is: (i) above the predetermined threshold: CD119, TRAIL.R2, CD54, or any combination thereof; (i) below the predetermined threshold: CD95; or (ii) any combination of (i) and (i);

[0121] (4) the level of VEGF is above the predetermined threshold; orAtny Docket No. ACTU-42816.601

[0122] (5) any combination of (1)-(4).

[0123] In some embodiments, the predetermined thresholds used in the above method is: (a) from about 1.0 to about 25 pg / mL for IL-6; (b) from about 8.0 to about 35 pg / mL for IL-8; (c) from about 150 to about 300 pg / mL for CCL2; (d) from about 325 to about 450 pg / mL for IL-34; (e) from about 85 to about 120 pg / mL for CD119; (f) from about 525 to about 725 pg / mL for CCL21; (g) from about 55 to about 90 pg / mL for TRAIL; (h) from about 65 to about 100 pg / mL for TRAIL.R2; (i) from about 30 to about 135 pg / mL for VEGF; (j) from about 415 to about 500 pg / mL for CXCL5; (k) from about 300,000 to about 450,000 pg / mL for CD54; (l) from about 300 to about 415 pg / mL for CCL3; (m) from about 9000 to about 10,500 pg / mL for CD95; (n) from about 100,000 to about 175,000 pg / mL for CHI3L1; or (o) from about 25 to about 45 pg / mL for IL-1 alpha.

[0124] In stil other embodiments, the predetermined thresholds used in the method is: (a) from about 1.0 to about 15 pg / mL for IL-6; (b) from about 10 to about 25 pg / mL for IL-8; (c) from about 175 to about 250 pg / mL for CCL2; (d) from about 350 to about 400 pg / mL for IL-34; (e) from about 85 to about 100 pg / mL for CD119; (f) from about 550 to about 650 pg / mL for CCL21; (g) from about 60 to about 85 pg / mL for TRAIL; (h) from about 70 to about 90 pg / mL for TRAIL.R2; (i) from about 30 to about 125 pg / mL for VEGF; (j) from about 425 to about 485 pg / mL for CXCL5; (k) from about 350,000 to about 425,000 pg / mL for CD54; (l) from about 325 to about 400 pg / mL for CCL3; (m) from about 9400 to about 10,000 pg / mL for CD95; (n) from about 125,000 to about 175,000 pg / mL for CHI3L1; or (o) from about 25 to about 40 pg / mL for IL-1 alpha.

[0125] In some embodiments, if pursuant to the above method, a patient is selected for treatment with elraglusib, the patient can be administered elraglusib in an amount of about 0.5 mg / kg, about 1 mg / kg, about 2 mg / kg, about 3 mg / kg, about 4 mg / kg, about 5 mg / kg, about 6 mg / kg, about 7 mg / kg, about 8 mg / kg, about 10 mg / kg, about 11 mg / kg, about 12 mg / kg, about 13 mg / kg, about 15 mg / kg, about 16 mg / kg, about 17 mg / kg, about 18 mg / kg, about 19 mg / kg, about 20 mg / kg, about 21 mg / kg, about 22 mg / kg, about 23 mg / kg, about 24 mg / kg, about 25 mg / kg, about 26 mg / kg, about 27 mg / kg, about 28 mg / kg, about 29 mg / kg, about 30 mg / kg, about 31 mg / kg, about 32 mg / kg, about 33 mg / kg, about 34 mg / kg, about 35 mg / kg, about 36 mg / kg, about 37 mg / kg, about 38 mg / kg, about 39 mg / kg, about 40 mg / kg, about 41 mg / kg, about 42 mg / kg, about 43 mg / kg, about 44 mg / kg about 45 mg / kg, about 46 mg / kg, about 47Atny Docket No. ACTU-42816.601 mg / kg, about 48 mg / kg, about 49 mg / kg or about 50 mg / kg, once, twice or three times per week (e.g., 7 days).

[0126] In some embodiments, if pursuant to the above method, a patient is not selected for treatment with elraglusib, the patient can be treated with the standard of care.

[0127] In some embodiments, the biological sample in the above is a liquid sample, a tumor biopsy sample, or a combination thereof.

[0128] In further embodiments, the liquid sample, is a whole blood sample, a plasma sample, a serum sample, a urine sample, or any combination thereof.

[0129] In some embodiments, the tumor biopsy sample is a brush cytology biopsy sample, or a piece of tumor tissue.

[0130] In certain embodiments, the patient is treated with a combination of elraglusib and a chemotherapeutic agent. In further embodiments, the chemotherapeutic agent is a taxane, a combination of leucovorin calcium, fluorouracil, irinotecan, and oxaliplatin, gemcitabine, a combination of gemcitabine and taxane, or a combination of irinotecan, leucovorin and fluorouracil.

[0131] In certain embodiments, the cancer is cancer of oral cavity, salivary gland cancer, esophageal cancer, galbladder cancer, cancer of bile ducts, liver cancer, stomach cancer, pancreatic cancer, colon cancer, rectal cancer, anal cancer, gastrointestinal stromal tumors, gastrointestinal carcinoid tumors, breast cancer, cervical cancer, endometrial cancer, ovarian cancer, and vaginal cancer, bladder cancer, testicular cancer, prostate cancer, kidney cancer, renal cel carcinoma, adrenal cancer, and penile cancer, thyroid cancer, eye cancer, retinoblastoma, skin cancer, basal cel carcinoma, melanoma, neuroendocrine tumor, neuroblastoma, head and neck cancer, nasal cancer, laryngeal cancer, lung cancer, malignant mesothelioma, aplastic anemia, Non-Hodgkin's lymphoma, Hodgkin's lymphoma, acute lymphocytic (lymphoblastic) leukemia, T-cel leukemia, acute myeloid leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, multiple myeloma, myelodysplastic syndrome, hairy cel leukemia, lymphoplasmacytic lymphoma (Waldenstrom's macroglobulinemia), tumors of central nervous system (CNS), glioblastoma, glioma, astrocytoma, meduloblastoma, CNS lymphoma, and pituitary tumor, bone cancer, osteosarcoma, rhabdomyosarcoma, sarcoma, or any combination thereof. In other aspects, the cancer is pancreatic cancer, a sarcoma, non-Hodgkin lymphoma, glioma, renal cancer, breast cancer, orAtny Docket No. ACTU-42816.601 any combination thereof. In stil some further aspects, the pancreatic cancer is metastatic pancreatic ductal adenocarcinoma (mPDAC).

[0132] Methods of Monitoring a Patient Sufering from Cancer and Receiving Treatment with Elraglusib

[0133] Also provided herein are methods of monitoring a patient sufering from cancer and receiving treatment with elraglusib. The first step of the method involves receiving information on whether a level of one or more cytokines, one or more chemokines, one or more soluble cel receptors, or one or more growth factors, or any combination thereof in a biological sample obtained from a patient sufering from cancer and curently receiving treatment with elraglusib is higher or lower than one or more predetermined thresholds (to its coresponding one or more cytokines, one or more chemokines, one or more soluble cel receptors, one or more growth factors, or any combination thereof). The one or more cytokines used in the method are IL-6, IL- 8, IL-34, TRAIL, CCL3, CHI3L1, IL-1 alpha, or any combination thereof. The one or more chemokines used in the method are CCL2, CCL21, CXCL5 or any combination thereof. The one or more soluble cel receptors used in the method are CD119, TRAIL.R2, CD54, CD95, or any combination thereof. The one or more growth factors used in the method if VEGF.

[0134] In some embodiments, the level (or amount) of one or more cytokines, one or more chemokines, one or more soluble cel receptors, growth factors, or any combination thereof, that is received can be determined using routine techniques known in the art. For example, the level (or amount) of one or more cytokines, on or more chemokines, one or more soluble receptors, growth factors, or any combination thereof can be determined by performing one or more of an immunoassay (e.g., such as a Luminex Immunoassay), a single molecule detection assay, protein immunoprecipitation, immunoelectrophoresis, chemical analysis, SDS-PAGE and Western blot analysis, or protein immunostaining, electrophoresis analysis, a protein assay, a competitive binding assay, a functional protein assay, a Meso Scale Discovery (MSD) immunoassay or chromatography or spectrometry methods, such as high-performance liquid chromatography (HPLC) or liquid chromatography-mass spectrometry (LC / MS) on the biological sample obtained from the patient. The level (or amount) of one or more cytokines, one or more chemokines, one or more soluble cel receptors, growth factors, or any combination thereof to be determined using these techniques can be done simultaneously or sequentialy and in any order.Atny Docket No. ACTU-42816.601

[0135] Once the level (or amount) of one or more cytokines, one or more chemokines, one or more soluble cel receptors, growth factors, or any combination thereof in a biological sample from a patient sufering from cancer is obtained, the level of each cytokine, chemokine, soluble cel receptor and / or growth factor is compared to a predetermined threshold to determine whether the level (or amount) of said cytokine, chemokine, soluble cel receptor and / or growth factor is above or below the predetermined threshold.

[0136] Once the level (or amount) of a cytokine, chemokine, soluble cel receptor and / or growth factor is determined to be above or below the predetermined threshold, a further determination is made of whether to continue to treat the patient with elraglusib. Specificaly, a determination is made that the patient should continue treatment with elraglusib if:

[0137] (1) the level of one or more of the folowing chemokines is: (i) below the predetermined threshold: IL-6, IL-8, IL-34, TRAIL, CCL3, CHI3L1, IL-1 alpha, or any combination thereof; (i) above the predetermined threshold: TRAIL; or (ii) any combination of (i) and (i);

[0138] (2) the level of one or more of the folowing chemokines is below the predetermined threshold: CCL2, CCL21, CXCL5 or any combination thereof;

[0139] (3) the level of one or more of the folowing soluble receptors is: (i) below the predetermined threshold: CD119, TRAIL.R2, CD54, or any combination thereof; (i) above the predetermined threshold: CD95; or (ii) any combination of (i) and (i);

[0140] (4) the level of VEGF is below the predetermined threshold; or

[0141] (5) any combination of (1)-(4).

[0142] In contrast, a determination is made that the patient should not continue treatment with elraglusib if:

[0143] (1) the level of one or more of the folowing chemokines is: (i) above the predetermined threshold: IL-6, IL-8, IL-34, CCL3, CHI3L1, IL-1 alpha, or any combination thereof; (i) below the predetermined threshold: TRAIL; or (ii) any combination of (i) and (i);

[0144] (2) the level of one or more of the folowing chemokines is above the predetermined threshold: CCL2, CCL21, CXCL5 or any combination thereof;

[0145] (3) the level of one or more of the folowing soluble receptors is: (i) above the predetermined threshold: CD119, TRAIL.R2, CD54, or any combination thereof; (i) below the predetermined threshold: CD95; or (ii) any combination of (i) and (i);Atny Docket No. ACTU-42816.601

[0146] (4) the level of VEGF is above the predetermined threshold; or

[0147] (5) any combination of (1)-(4).

[0148] In some embodiments, the predetermined thresholds used in the above method is: (a) from about 1.0 to about 25 pg / mL for IL-6; (b) from about 8.0 to about 35 pg / mL for IL-8; (c) from about 150 to about 300 pg / mL for CCL2; (d) from about 325 to about 450 pg / mL for IL-34; (e) from about 85 to about 120 pg / mL for CD119; (f) from about 525 to about 725 pg / mL for CCL21; (g) from about 55 to about 90 pg / mL for TRAIL; (h) from about 65 to about 100 pg / mL for TRAIL.R2; (i) from about 30 to about 135 pg / mL for VEGF; (j) from about 415 to about 500 pg / mL for CXCL5; (k) from about 300,000 to about 450,000 pg / mL for CD54; (l) from about 300 to about 415 pg / mL for CCL3; (m) from about 9000 to about 10,500 pg / mL for CD95; (n) from about 100,000 to about 175,000 pg / mL for CHI3L1; or (o) from about 25 to about 45 pg / mL for IL-1 alpha.

[0149] In stil other embodiments, the predetermined thresholds used in the method is: (a) from about 1.0 to about 15 pg / mL for IL-6; (b) from about 10 to about 25 pg / mL for IL-8; (c) from about 175 to about 250 pg / mL for CCL2; (d) from about 350 to about 400 pg / mL for IL-34; (e) from about 85 to about 100 pg / mL for CD119; (f) from about 550 to about 650 pg / mL for CCL21; (g) from about 60 to about 85 pg / mL for TRAIL; (h) from about 70 to about 90 pg / mL for TRAIL.R2; (i) from about 30 to about 125 pg / mL for VEGF; (j) from about 425 to about 485 pg / mL for CXCL5; (k) from about 350,000 to about 425,000 pg / mL for CD54; (l) from about 325 to about 400 pg / mL for CCL3; (m) from about 9400 to about 10,000 pg / mL for CD95; (n) from about 125,000 to about 175,000 pg / mL for CHI3L1; or (o) from about 25 to about 40 pg / mL for IL-1 alpha.

[0150] In some embodiments, if pursuant to the above method, it is determined that the patient is to continue with treatment with elraglusib, then the patient can continue on their specific dosing regimen. Alternatively, the dosing regimen of the patient can be altered such that the patient is administered elraglusib in an amount of about 0.5 mg / kg, about 1 mg / kg, about 2 mg / kg, about 3 mg / kg, about 4 mg / kg, about 5 mg / kg, about 6 mg / kg, about 7 mg / kg, about 8 mg / kg, about 10 mg / kg, about 11 mg / kg, about 12 mg / kg, about 13 mg / kg, about 15 mg / kg, about 16 mg / kg, about 17 mg / kg, about 18 mg / kg, about 19 mg / kg, about 20 mg / kg, about 21 mg / kg, about 22 mg / kg, about 23 mg / kg, about 24 mg / kg, about 25 mg / kg, about 26 mg / kg, about 27 mg / kg, about 28 mg / kg, about 29 mg / kg, about 30 mg / kg, about 31 mg / kg, about 32Atny Docket No. ACTU-42816.601 mg / kg, about 33 mg / kg, about 34 mg / kg, about 35 mg / kg, about 36 mg / kg, about 37 mg / kg, about 38 mg / kg, about 39 mg / kg, about 40 mg / kg, about 41 mg / kg, about 42 mg / kg, about 43 mg / kg, about 44 mg / kg about 45 mg / kg, about 46 mg / kg, about 47 mg / kg, about 48 mg / kg, about 49 mg / kg or about 50 mg / kg, once, twice or three times per week (e.g., 7 days).

[0151] In some embodiments, if pursuant to the above method, it is determined that the patient should not continue to be treated with elraglusib, then patient can be switched to the standard of care.

[0152] In some embodiments, the biological sample in the above is a liquid sample, a tumor biopsy sample, or a combination thereof.

[0153] In further embodiments, the liquid sample, is a whole blood sample, a plasma sample, a serum sample, a urine sample, or any combination thereof.

[0154] In some embodiments, the tumor biopsy sample is a brush cytology biopsy sample, or a piece of tumor tissue.

[0155] In certain embodiments, the patient is treated with a combination of elraglusib and a chemotherapeutic agent. In further embodiments, the chemotherapeutic agent is a taxane, a combination of leucovorin calcium, fluorouracil, irinotecan, and oxaliplatin, gemcitabine, a combination of gemcitabine and taxane, or a combination of irinotecan, leucovorin and fluorouracil.

[0156] In certain embodiments, the cancer is cancer of oral cavity, salivary gland cancer, esophageal cancer, galbladder cancer, cancer of bile ducts, liver cancer, stomach cancer, pancreatic cancer, colon cancer, rectal cancer, anal cancer, gastrointestinal stromal tumors, gastrointestinal carcinoid tumors, breast cancer, cervical cancer, endometrial cancer, ovarian cancer, and vaginal cancer, bladder cancer, testicular cancer, prostate cancer, kidney cancer, renal cel carcinoma, adrenal cancer, and penile cancer, thyroid cancer, eye cancer, retinoblastoma, skin cancer, basal cel carcinoma, melanoma, neuroendocrine tumor, neuroblastoma, head and neck cancer, nasal cancer, laryngeal cancer, lung cancer, malignant mesothelioma, aplastic anemia, Non-Hodgkin's lymphoma, Hodgkin's lymphoma, acute lymphocytic (lymphoblastic) leukemia, T-cel leukemia, acute myeloid leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, multiple myeloma, myelodysplastic syndrome, hairy cel leukemia, lymphoplasmacytic lymphoma (Waldenstrom's macroglobulinemia), tumors of central nervous system (CNS), glioblastoma, glioma,Atny Docket No. ACTU-42816.601 astrocytoma, meduloblastoma, CNS lymphoma, and pituitary tumor, bone cancer, osteosarcoma, rhabdomyosarcoma, sarcoma, or any combination thereof. In other aspects, the cancer is pancreatic cancer, a sarcoma, non-Hodgkin lymphoma, glioma, renal cancer, breast cancer, or any combination thereof. In stil some further aspects, the pancreatic cancer is metastatic pancreatic ductal adenocarcinoma (mPDAC). EXAMPLES

[0157] The folowing examples are for the purposes of ilustration only and are not intended to limit the scope of the claims. EXAMPLE 1

[0158] In Part 1-2 of 1801 clinical study, baseline plasma samples were obtained from 45 patients with relapsed / refractory metastatic disease (e.g., pancreatic cancer, breast cancer, colorectal cancer, esophageal cancer, lung cancer, ovarian cancer, uterine cancer, head and neck cancer, glioblastoma, melanoma) before treatment (Cycle 1 Day 1).

[0159] Using a commercialy available immunoassay, the level of 40 cytokines / chemokines / soluble cel receptors / growth factors (CCSGs) were obtained for the 45 patients. Al patients were treated with elraglusib (dose range: 1-15 mg / kg) either as a single agent (Part 1; n=21) or in combination with chemotherapy (Part 2; n=24). The chemotherapy used was gemcitabine (a 21-day cycle or a 28-day cycle), doxorubicin, lomustine, carboplatin, nab-paclitaxel, paclitaxel or irinotecan. Pre-dose peripheral blood protein levels were examined as binary predictors of clinical outcome using optimal predetermined thresholds (e.g., cutof points) determined by maximaly selected rank statistics. CCSGs that significantly stratified the cohort by overal survival (OS) are listed in Table 1.

[0160] In a further clinical study (Part 3), CCSGs were evaluated in the pre-dose plasma samples from 45 patients newly diagnosed with metastatic pancreatic ductal adenocarcinoma (mPDAC) and treated with gemcitabine / nab-paclitaxel (GnP) (n = 13) or elraglusib+GnP (n = 32). Using a commercialy available immunoassay, 40 CCSGs were screened as predictive biomarkers of median overal survival (mOS) in the elraglusib+GnP arm using 5-fold cross- validation and maximaly selected rank statistic cutpoint determination. A subset of CCSGs (n = 10) was remeasured using a second commercialy available immunoassay with greater sensitivity. Maximaly selected rank statistic cutpoint determinations were conducted using theAtny Docket No. ACTU-42816.601 results from the immunoassay with greater sensitivity for elraglusib+GnP samples with mOS and median progression free survival (mPFS). P values < 0.05 were considered statisticaly significant. CCSGs that significantly stratified the cohort by mOS are listed below in Table 1.

[0161] It was found that levels of cytokines, chemokines, soluble cel receptors, and / or growth factors above or below (e.g., higher or lower) a predetermined threshold (e.g., cutpoint) as shown in Table 1 could serve as predictive biomarkers of a beter survival in subjects receiving elraglusib or elraglusib in combination with chemotherapy in cancer patients with metastatic disease as wel as for selecting patients sufering from cancer for treatment with elraglusib. Specificaly, as shown in Table 1, in patients treated with elraglusib or elraglusib+chemotherapy (Part 1-2) and elraglusib+GnP (Part 3B), high expression level of selected CCSGs above a predetermined threshold (e.g., cutpoint) indicated as “unfavorable” means worse OS whereas low expression level of the same CCSG below a predetermined threshold (e.g., cutpoint) is “favorable” meaning beter OS. For selected CCSGs (CD95, TRAIL), high expression level of selected CCSGs above a predetermined threshold (e.g., cutpoint) indicated as “favorable” means beter OS whereas high expression level of the same CCSG above a predetermined threshold (e.g., cutpoint) is “unfavorable” meaning worse OS.

[0162] Table 1. CCSG expression level and clinical outcome in cancer patients treated with elraglusib alone or combination of elraglusib and chemotherapeutic drugs. Clinical outcome for e h l,Atny Docket No. ACTU-42816.601 CCL3 Cytokine 350 Unfavorable NA, P>0.05 CD95 Soluble cel receptor 9800 Favorable NA, P>0.05xamples are merely ilustrative and are not to be taken as limitations upon the scope of the disclosure, which is defined solely by the appended claims and their equivalents.

[0164] Various changes and modifications to the disclosed embodiments wil be apparent to those skiled in the art and may be made without departing from the spirit and scope thereof.

Claims

Atny Docket No. ACTU-42816.601 We claim:

1. A method of treating a subject sufering from cancer, the method comprising the steps of: a. receiving information on whether a level of one or more cytokines, one or more chemokines, one or more soluble cel receptors, or one or more growth factors, or any combination thereof in a biological sample obtained from a subject sufering from cancer is higher or lower than one or more predetermined thresholds, wherein the one or more cytokines are IL-6, IL-8, IL-34, TRAIL, CCL3, CHI3L1, IL-1 alpha, or any combination thereof, the one or more chemokines are CCL2, CCL21, CXCL5 or any combination thereof, the one or more soluble cel receptor is CD119, TRAIL.R2, CD54, CD95, or any combination thereof, and the growth factor is VEGF; and b. administering elraglusib to the subject if: (1) the level of one or more of the folowing chemokines is: (i) below the predetermined threshold: IL-6, IL-8, IL-34, TRAIL, CCL3, CHI3L1, IL-1 alpha, or any combination thereof; (i) above the predetermined threshold: TRAIL; or (ii) any combination of (i) and (i); (2) the level of one or more of the folowing chemokines is below the predetermined threshold: CCL2, CCL21, CXCL5 or any combination thereof; (3) the level of one or more of the folowing soluble receptors is: (i) below the predetermined threshold: CD119, TRAIL.R2, CD54, or any combination thereof; (i) above the predetermined threshold: CD95; or (ii) any combination of (i) and (i); (4) the level of VEGF is below the predetermined threshold; or (5) any combination of (1)-(4); or c. not administering elraglusib to the subject if: (1) the level of one or more of the folowing chemokines is: (i) above the predetermined threshold: IL-6, IL-8, IL-34, CCL3, CHI3L1, IL-1 alpha, or any combination thereof; (i) below the predetermined threshold: TRAIL; or (ii) any combination of (i) and (i); (2) the level of one or more of the folowing chemokines is above the predetermined threshold: CCL2, CCL21, CXCL5 or any combination thereof;Atny Docket No. ACTU-42816.601 (3) the level of one or more of the folowing soluble receptors is: (i) above the predetermined threshold: CD119, TRAIL.R2, CD54, or any combination thereof; (i) below the predetermined threshold: CD95; or (ii) any combination of (i) and (i); (4) the level of VEGF is above the predetermined threshold; or (5) any combination of (1)-(4).

2. The method of claim 1, wherein the predetermined threshold is: a. from about 1.0 to about 25 pg / mL for IL-6; b. from about 8.0 to about 35 pg / mL for IL-8; c. from about 150 to about 300 pg / mL for CCL2; d. from about 325 to about 450 pg / mL for IL-34; e. from about 85 to about 120 pg / mL for CD119; f. from about 525 to about 725 pg / mL for CCL21; g. from about 55 to about 90 pg / mL for TRAIL; h. from about 65 to about 100 pg / mL for TRAIL.R2; i. from about 30 to about 135 pg / mL for VEGF; j. from about 415 to about 500 pg / mL for CXCL5; k. from about 300,000 to about 450,000 pg / mL for CD54; l. from about 300 to about 415 pg / mL for CCL3; m. from about 9000 to about 10,500 pg / mL for CD95; n. from about 100,000 to about 175,000 pg / mL for CHI3L1; or o. from about 25 to about 45 pg / mL for IL-1 alpha.

3. The method of claim 1 or claim 2, wherein the biological sample is a liquid sample, a tumor biopsy sample, or a combination thereof.

4. The method of claim 3, wherein the liquid sample, is whole blood sample a plasma sample, a serum sample, a urine sample, or any combination thereof.

5. The method of claim 3, wherein the tumor biopsy sample is a brush cytology biopsy sample, or a piece of tumor tissue.

6. The method of any of claims 1-5, wherein the subject is treated with a combination of elraglusib and a chemotherapeutic agent.

7. The method of claim 6, wherein the chemotherapeutic agent is a taxane, a combination of leucovorin calcium, fluorouracil, irinotecan, and oxaliplatin, gemcitabine, aAtny Docket No. ACTU-42816.601 combination of gemcitabine and taxane, or a combination of irinotecan, leucovorin and fluorouracil.

8. The method of claim 7, wherein the taxane is paclitaxel, nab-paclitaxel, or a combination thereof.

9. The method of any of claims 1-8, wherein the cancer is cancer of oral cavity, salivary gland cancer, esophageal cancer, galbladder cancer, cancer of bile ducts, liver cancer, stomach cancer, pancreatic cancer, colon cancer, rectal cancer, anal cancer, gastrointestinal stromal tumors, gastrointestinal carcinoid tumors, breast cancer, cervical cancer, endometrial cancer, ovarian cancer, and vaginal cancer, bladder cancer, testicular cancer, prostate cancer, kidney cancer, renal cel carcinoma, adrenal cancer, and penile cancer, thyroid cancer, eye cancer, retinoblastoma, skin cancer, basal cel carcinoma, melanoma, neuroendocrine tumor, neuroblastoma, head and neck cancer, nasal cancer, laryngeal cancer, lung cancer, malignant mesothelioma, aplastic anemia, Non-Hodgkin's lymphoma, Hodgkin's lymphoma, acute lymphocytic (lymphoblastic) leukemia, T-cel leukemia, acute myeloid leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, multiple myeloma, myelodysplastic syndrome, hairy cel leukemia, lymphoplasmacytic lymphoma (Waldenstrom's macroglobulinemia), tumors of central nervous system (CNS), glioblastoma, glioma, astrocytoma, meduloblastoma, CNS lymphoma, and pituitary tumor, bone cancer, osteosarcoma, rhabdomyosarcoma, sarcoma, or any combination thereof.

10. A method of selecting a subject sufering from cancer for treatment with elraglusib, the method comprising the steps of: a. receiving information on whether a level of one or more cytokines, one or more chemokines, one or more soluble cel receptors, or one or more growth factors, or any combination thereof in a biological sample obtained from a subject sufering from cancer is higher or lower than one or more predetermined thresholds, wherein the one or more cytokines are IL-6, IL-8, IL-34, TRAIL, CCL3, CHI3L1, IL-1 alpha, or any combination thereof, the one or more chemokines are CCL2, CCL21, CXCL5 or any combination thereof, the one or more soluble cel receptor is CD119, TRAIL.R2, CD54, CD95, or any combination thereof, and the growth factor is VEGF; and b. selecting a subject for treatment with elraglusib if:Atny Docket No. ACTU-42816.601 (1) the level of one or more of the folowing chemokines is: (i) below the predetermined threshold: IL-6, IL-8, IL-34, TRAIL, CCL3, CHI3L1, IL-1 alpha, or any combination thereof; (i) above the predetermined threshold: TRAIL; or (ii) any combination of (i) and (i); (2) the level of one or more of the folowing chemokines is below the predetermined threshold: CCL2, CCL21, CXCL5 or any combination thereof; (3) the level of one or more of the folowing soluble receptors is: (i) below the predetermined threshold: CD119, TRAIL.R2, CD54, or any combination thereof; (i) above the predetermined threshold: CD95; or (ii) any combination of (i) and (i); (4) the level of VEGF is below the predetermined threshold; or (5) any combination of (1)-(4); or d. not selecting a subject for treatment with elraglusib if: (1) the level of one or more of the folowing chemokines is: (i) above the predetermined threshold: IL-6, IL-8, IL-34, CCL3, CHI3L1, IL-1 alpha, or any combination thereof; (i) below the predetermined threshold: TRAIL; or (ii) any combination of (i) and (i); (2) the level of one or more of the folowing chemokines is above the predetermined threshold: CCL2, CCL21, CXCL5 or any combination thereof; (3) the level of one or more of the folowing soluble receptors is: (i) above the predetermined threshold: CD119, TRAIL.R2, CD54, or any combination thereof; (i) below the predetermined threshold: CD95; or (ii) any combination of (i) and (i); (4) the level of VEGF is above the predetermined threshold; or (5) any combination of (1)-(4).

11. The method of claim 10, wherein the predetermined threshold is: a. from about 1.0 to about 25 pg / mL for IL-6; b. from about 8.0 to about 35 pg / mL for IL-8; c. from about 150 to about 300 pg / mL for CCL2; d. from about 325 to about 450 pg / mL for IL-34; e. from about 85 to about 120 pg / mL for CD119; f. from about 525 to about 725 pg / mL for CCL21; g. from about 55 to about 90 pg / mL for TRAIL;Atny Docket No. ACTU-42816.601 h. from about 65 to about 100 pg / mL for TRAIL.R2; i. from about 30 to about 135 pg / mL for VEGF; j. from about 415 to about 500 pg / mL for CXCL5; k. from about 300,000 to about 450,000 pg / mL for CD54; l. from about 300 to about 415 pg / mL for CCL3; m. from about 9000 to about 10,500 pg / mL for CD95; n. from about 100,000 to about 175,000 pg / mL for CHI3L1; or o. from about 25 to about 45 pg / mL for IL-1 alpha.

12. The method of claim 10 or claim 11, wherein the biological sample is a liquid sample, a tumor biopsy sample, or a combination thereof.

13. The method of claim 12, wherein the liquid sample, is whole blood sample a plasma sample, a serum sample, a urine sample, or any combination thereof.

14. The method of claim 12, wherein the tumor biopsy sample is a brush cytology biopsy sample, or a piece of tumor tissue.

15. The method of any of claims 10-14, wherein the subject is treated with a combination of elraglusib and a chemotherapeutic agent.

16. The method of claim 15, wherein the chemotherapeutic agent is a taxane, a combination of leucovorin calcium, fluorouracil, irinotecan, and oxaliplatin, gemcitabine, a combination of gemcitabine and taxane, or a combination of irinotecan, leucovorin and fluorouracil.

17. The method of claim 16, wherein the taxane is paclitaxel, nab-paclitaxel, or a combination thereof.

18. The method of any of claims 10-17, wherein the cancer is cancer of oral cavity, salivary gland cancer, esophageal cancer, galbladder cancer, cancer of bile ducts, liver cancer, stomach cancer, pancreatic cancer, colon cancer, rectal cancer, anal cancer, gastrointestinal stromal tumors, gastrointestinal carcinoid tumors, breast cancer, cervical cancer, endometrial cancer, ovarian cancer, and vaginal cancer, bladder cancer, testicular cancer, prostate cancer, kidney cancer, renal cel carcinoma, adrenal cancer, and penile cancer, thyroid cancer, eye cancer, retinoblastoma, skin cancer, basal cel carcinoma, melanoma, neuroendocrine tumor, neuroblastoma, head and neck cancer, nasal cancer, laryngeal cancer, lung cancer, malignant mesothelioma, aplastic anemia, Non-Hodgkin's lymphoma, Hodgkin's lymphoma, acuteAtny Docket No. ACTU-42816.601 lymphocytic (lymphoblastic) leukemia, T-cel leukemia, acute myeloid leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, multiple myeloma, myelodysplastic syndrome, hairy cel leukemia, lymphoplasmacytic lymphoma (Waldenstrom's macroglobulinemia), tumors of central nervous system (CNS), glioblastoma, glioma, astrocytoma, meduloblastoma, CNS lymphoma, and pituitary tumor, bone cancer, osteosarcoma, rhabdomyosarcoma, sarcoma, or any combination thereof.

19. A method of monitoring a subject sufering from cancer and receiving treatment with elraglusib, the method comprising the steps of: a. receiving information on whether a level of one or more cytokines, one or more chemokines, one or more soluble cel receptors, or one or more growth factors, or any combination thereof in a biological sample obtained from a subject sufering from cancer and receiving treatment with elraglusib is higher or lower than one or more predetermined thresholds, wherein the one or more cytokines are IL-6, IL-8, IL-34, TRAIL, CCL3, CHI3L1, IL-1 alpha, or any combination thereof, the one or more chemokines are CCL2, CCL21, CXCL5 or any combination thereof, the one or more soluble cel receptor is CD119, TRAIL.R2, CD54, CD95, or any combination thereof, and the growth factor is VEGF; and b. continuing to treat the subject with elraglusib, if: (1) the level of one or more of the folowing chemokines is: (i) below the predetermined threshold: IL-6, IL-8, IL-34, TRAIL, CCL3, CHI3L1, IL-1 alpha, or any combination thereof; (i) above the predetermined threshold: TRAIL; or (ii) any combination of (i) and (i); (2) the level of one or more of the folowing chemokines is below the predetermined threshold: CCL2, CCL21, CXCL5 or any combination thereof; (3) the level of one or more of the folowing soluble receptors is: (i) below the predetermined threshold: CD119, TRAIL.R2, CD54, or any combination thereof; (i) above the predetermined threshold: CD95; or (ii) any combination of (i) and (i); (4) the level of VEGF is below the predetermined threshold; or (5) any combination of (1)-(4); or c. discontinuing to treat the subject to elraglusib, if: (1) the level of one or more of the folowing chemokines is: (i) above the predetermined threshold: IL-6, IL-8, IL-34, CCL3, CHI3L1, IL-1 alpha, or anyAtny Docket No. ACTU-42816.601 combination thereof; (i) below the predetermined threshold: TRAIL; or (ii) any combination of (i) and (i); (2) the level of one or more of the folowing chemokines is above the predetermined threshold: CCL2, CCL21, CXCL5 or any combination thereof; (3) the level of one or more of the folowing soluble receptors is: (i) above the predetermined threshold: CD119, TRAIL.R2, CD54, or any combination thereof; (i) below the predetermined threshold: CD95; or (ii) any combination of (i) and (i); (4) the level of VEGF is above the predetermined threshold; or (5) any combination of (1)-(4).

20. The method of claim 19, wherein the predetermined threshold is: a. from about 1.0 to about 25 pg / mL for IL-6; b. from about 8.0 to about 35 pg / mL for IL-8; c. from about 150 to about 300 pg / mL for CCL2; d. from about 325 to about 450 pg / mL for IL-34; e. from about 85 to about 120 pg / mL for CD119; f. from about 525 to about 725 pg / mL for CCL21; g. from about 55 to about 90 pg / mL for TRAIL; h. from about 65 to about 100 pg / mL for TRAIL.R2; i. from about 30 to about 135 pg / mL for VEGF; j. from about 415 to about 500 pg / mL for CXCL5; k. from about 300,000 to about 450,000 pg / mL for CD54; l. from about 300 to about 415 pg / mL for CCL3; m. from about 9000 to about 10,500 pg / mL for CD95; n. from about 100,000 to about 175,000 pg / mL for CHI3L1; or o. from about 25 to about 45 pg / mL for IL-1 alpha.

21. The method of claim 19 or claim 20, wherein the biological sample is a liquid sample, a tumor biopsy sample, or a combination thereof.

22. The method of claim 21, wherein the liquid sample, is whole blood sample a plasma sample, a serum sample, a urine sample, or any combination thereof.

23. The method of claim 21, wherein the tumor biopsy sample is a brush cytology biopsy sample, or a piece of tumor tissue.Atny Docket No. ACTU-42816.601 24. The method of any of claims 19-23, wherein the subject is treated with a combination of elraglusib and a chemotherapeutic agent.

25. The method of claim 24, wherein the chemotherapeutic agent is a taxane, a combination of leucovorin calcium, fluorouracil, irinotecan, and oxaliplatin, gemcitabine, a combination of gemcitabine and taxane, or a combination of irinotecan, leucovorin and fluorouracil.

26. The method of claim 25, wherein the taxane is paclitaxel, nab-paclitaxel, or a combination thereof.

27. The method of any of claims 19-26, wherein the cancer is cancer of oral cavity, salivary gland cancer, esophageal cancer, galbladder cancer, cancer of bile ducts, liver cancer, stomach cancer, pancreatic cancer, colon cancer, rectal cancer, anal cancer, gastrointestinal stromal tumors, gastrointestinal carcinoid tumors, breast cancer, cervical cancer, endometrial cancer, ovarian cancer, and vaginal cancer, bladder cancer, testicular cancer, prostate cancer, kidney cancer, renal cel carcinoma, adrenal cancer, and penile cancer, thyroid cancer, eye cancer, retinoblastoma, skin cancer, basal cel carcinoma, melanoma, neuroendocrine tumor, neuroblastoma, head and neck cancer, nasal cancer, laryngeal cancer, lung cancer, malignant mesothelioma, aplastic anemia, Non-Hodgkin's lymphoma, Hodgkin's lymphoma, acute lymphocytic (lymphoblastic) leukemia, T-cel leukemia, acute myeloid leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, multiple myeloma, myelodysplastic syndrome, hairy cel leukemia, lymphoplasmacytic lymphoma (Waldenstrom's macroglobulinemia), tumors of central nervous system (CNS), glioblastoma, glioma, astrocytoma, meduloblastoma, CNS lymphoma, and pituitary tumor, bone cancer, osteosarcoma, rhabdomyosarcoma, sarcoma, or any combination thereof.

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