Methods of treating cancer with farnesyltransferase inhibitors

An inhibitor, cancer technology, applied in the field of cancer therapy, can solve problems such as unmet sexual needs

Pending Publication Date: 2021-08-20
KURA ONCOLOGY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

However, patients respond differently to FTI therapy
Therefore, methods of predicting the responsiveness of subj

Method used

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  • Methods of treating cancer with farnesyltransferase inhibitors
  • Methods of treating cancer with farnesyltransferase inhibitors
  • Methods of treating cancer with farnesyltransferase inhibitors

Examples

Experimental program
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Embodiment 1

[0461] Example 1: Crosstalk between the IGF1 and CXCL12 pathways defines targeted responses to the farnesyltransferase inhibitor tipifarnib in AML and PTCL patients

[0462] Results were analyzed using RNA-Seq and Affymetrix U133A microarray analysis of tumor samples from 71 patients enrolled in the Tipifarnib trials (CTEP-20, KO-TIP-002, KO-TIP-004). Gene Expression Profile (GEP) data, and complement the analysis of mRNA expression in datasets from cBioportal for Cancer Genomics. Clinical trial information: NCT00027872, NCT02464228, NCT02807272.

[0463] The pathology of tumor CXCL12 overexpression was explored by examining the gene expression signature (available at cBioportal (TCGA, Provisional)) of 8,401 cancer patients in 25 studies. In 19 of these studies, the expression of IGF1 and CXCL12 genes A highly significant correlation was present. These 25 studies are detailed in Table 1 below. The highly significant correlation between IGF1 and CXCL12 gene expression in breas...

Embodiment 2

[0476] Example 2: Identification of clinical and molecular biomarkers associated with clinical benefit of tipifarnib in advanced pancreatic cancer.

[0477] as table 1 and figure 1 As seen in , patients with pancreatic cancer showed a high correlation between the CXCL12 and IGF1 genes and higher than other tumor types for which tipifarnib activity has been observed. Pancreatic tumors also express very high levels of IGFB7. IGFBP7 was found to be co-expressed in these tumors with IGF1 (p=0.643, p<0.0001, N=179) and CXCL12 (p=0.617, p<0.0001, N=173).

[0478] In a randomized, double-blind, placebo-controlled study of gemcitabine + tipifarnib versus gemcitabine + placebo in patients with advanced pancreatic adenocarcinoma not previously treated with systemic Tipifarnib (R115777) was administered at a dose of 200 mg (Study INT-17). Gemcitabine was administered intravenously at a dose of 1,000 mg / m(2) 7 times a week for 8 weeks, then 3 times a week every 4 weeks.

[0479] 686 p...

Embodiment 3

[0488] Example 3: Low KRAS Mutant Allele Frequency Identifies Pancreatic Cancer Patients at Potential for Clinical Benefit of Tipifarnib

[0489] Low KRAS mutant allele frequency in pancreatic tumor samples is associated with high CXCL12 and high IGF1 gene expression. However, IGFBP7 is highly expressed in pancreatic cancer overall, but tends to increase with decreasing KRAS mutant allele frequency ( Figure 7A ). Thus, low KRAS mutant allele frequencies may identify pancreatic cancer patients with high CXCL12 who are susceptible to the clinical benefit of tipifarnib. Likewise, low KRAS mutant allele frequency identifies pancreatic cancer patients with the highest IGFBP7 expression, which blocks any potential tipifarnib resistance mediated by IGF1 ( Figure 7A ).

[0490] CXCL12 expression was also elevated in tumors with wild-type TP53 status or TP53 mutations with low allele frequency ( Figure 7B , left). The optimal cutoff for the TP53 mutant allele frequency for CXCL...

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Abstract

The present invention relates to the field of cancer therapy. Specifically, provided are methods of treating cancer in a subject with a farnesyltransferase inhibitor (FTI) that include determining whether the subject is likely to be responsive to the FTI treatment based on the activity of the CXCL12/CXCR4 pathway, and/or the activity of the IGF1R pathway. Provided herein are also combination therapy of cancer treatment using FTI and either an IGF1R inhibitor or a CXCR4 antagonist.

Description

[0001] This application claims the benefit of priority to U.S. Provisional Application No. 62 / 754,438, filed November 01, 2018, and U.S. Provisional Application No. 62 / 793,547, filed January 17, 2019, the entire contents of which are incorporated by reference into this article. technical field [0002] The present invention relates to the field of cancer therapy. In particular, provided herein are methods of treating cancer with farnesyltransferase inhibitors. Background technique [0003] Stratification of patient populations to improve treatment response rates is increasingly valuable in the clinical management of cancer patients. Farnesyltransferase inhibitors (FTIs) are therapeutic agents that have been used to treat cancer. However, patients respond differently to FTI therapy. Therefore, methods of predicting the responsiveness of subjects with cancer to FTI therapy or methods of selecting cancer patients for FTI therapy represent an unmet need. The methods and comp...

Claims

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Application Information

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IPC IPC(8): A61K31/4704A61K45/06A61P35/00
CPCA61K31/4704A61K45/06A61P35/00A61K2300/00A61K31/4709A61K31/4545A61K31/551A61K31/7068A61P35/02A61K31/05A61K31/223A61K31/352A61K31/365A61K31/366A61K31/395A61K31/404A61K31/427A61K31/437A61K31/4406A61K31/4418A61K31/4706A61K31/4745A61K31/496A61K31/498A61K31/519A61K31/52A61K31/53A61K31/5377A61K31/5513A61K31/675A61K31/7064A61K38/07A61K38/12A61K39/3955C07K16/22
Inventor 安东尼奥·瓜尔贝托
Owner KURA ONCOLOGY
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