BIOMARKERS FOR RESPONSE TO TYROSINE KINASE PATHWAY INHIBITORS IN CANCER

• US 20130230511A1
• Filed: 02/04/2013
• Published: 09/05/2013
• Est. Priority Date: 02/03/2012
• Status: Abandoned Application

• Current Assignee: Board of Regents of the University of Texas System (University of Texas System)
• Original Assignee: Board of Regents of the University of Texas System (University of Texas System)
• Inventors: HEYMACH, John V., WISTUBA, Ignacio I., NILSSON, Monique B., BYERS, Lauren A., TANG, Ximing, YANG, Fei, KIM, Edward, TSAO, Anne S., LIPPMAN, Scott M., HONG, Waun Ki, HERBST, Roy S.
• Application Number:
  US13/758,728
• Publication Number:
  US 20130230511A1
• Time in Patent Office: Days
• US Class Current: 424/133.1
• CPC Class Codes: A61K 31/404 Indoles, e.g. pindolol
• CPC Class Codes: A61K 31/4045 Indole-alkylamines; Amides thereof, e.g. serotonin, melatonin
• CPC Class Codes: A61K 31/44 Non condensed pyridines; Hydrogenated derivatives thereof
• CPC Class Codes: A61K 31/4439 containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole nicotine A61K31/465
• CPC Class Codes: A61K 31/444 containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
• CPC Class Codes: A61K 31/4709 Non-condensed quinolines and containing further heterocyclic rings
• CPC Class Codes: A61K 31/496 Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
• CPC Class Codes: A61K 31/502 ortho- or peri-condensed with carbocyclic ring systems, e.g. cinnoline, phthalazine
• CPC Class Codes: A61K 31/506 not condensed and containing further heterocyclic rings
• CPC Class Codes: A61K 39/39558 against tumor tissues, cells, antigens
• CPC Class Codes: C07K 16/2863 against receptors for growth factors, growth regulators
• CPC Class Codes: C12Q 1/6886 for cancer immunoassay for cancer G01N33/574
• CPC Class Codes: C12Q 2600/106 Pharmacogenomics, i.e. genetic variability in individual responses to drugs and drug metabolism
• CPC Class Codes: C12Q 2600/118 Prognosis of disease development
• CPC Class Codes: C12Q 2600/156 Polymorphic or mutational markers
• CPC Class Codes: G01N 2800/52 Predicting or monitoring the response to treatment, e.g. for selection of therapy based on assay results in personalised medicine; Prognosis
• CPC Class Codes: G01N 33/57484 involving compounds serving as markers for tumor, cancer, neoplasia, e.g. cellular determinants, receptors, heat shock/stress proteins, A-protein, oligosaccharides, metabolites
• CPC Class Codes: G01N 33/74 involving hormones or other non-cytokine intercellular protein regulatory factors such as growth factors, including receptors to hormones and growth factors

Abstract

Copy number gains detected in tumors and associated with drug sensitivity and resistance in vivo and in vitro can be used as biomarkers to select, predict and monitor drug treatment outcomes in cancer patients treated with tyrosine kinase inhibitors. Methods to identify patients with NSCLC or other malignancies who are more likely to benefit from tyrosine kinase inhibitors such as VEGF or VEGFR inhibitors when used either as monotherapy or in combination with other therapies such as chemotherapy or EGFR inhibitors, and who are in the advanced stages of disease and/or who have undergone adjuvant therapy are also provided herein.

Claims

1. A method of treating a cancer patient comprising:

(a) selecting a patient determined to have a cancer with an elevated KDR, PDGFR, or KIT level; and

(b) treating the patient with a VEGF/VEGFR, PDGFR, or KIT pathway inhibitor.

2. The method of claim 1, wherein the elevated KDR, PDGFR, or KIT level is further defined as a gain in gene copy number, increased mRNA expression, or increased protein expression.

3. The method of claim 1, wherein the elevated KDR level is further defined as an increased mRNA or protein level of a KDR-regulated gene.

4. The method of claim 3, wherein the KDR-regulated gene is HIF-1α

.

5. The method of claim 1, wherein the cancer patient has a NSCLC or glioblastoma.

6. The method of claim 1, wherein the cancer is metastatic.

7. The method of claim 1, wherein the patient is treated with a VEGF/VEGFR pathway inhibitor.

8. The method of claim 1, wherein the patient is treated with a combination of two or more VEGF/VEGFR, PDGFR, or KIT pathway inhibitors.

9. The method of claim 1, further comprising treating the patient with a second anti-cancer therapy.

10. The method of claim 9, wherein the second anti-cancer therapy is not a platinum-based chemotherapeutic agent or an EGFR inhibitor.

11. The method of claim 1, wherein the patient has undergone surgery or radiotherapy and the treatment is an adjuvant treatment.

12. The method of claim 1, wherein the VEGF/VEGFR pathway inhibitor is ramucirumab, sunitinib, bevacizumab, aflibercept, BIBF1120, sorafenib, cediranib, dovitinib, pazopanib, ponatinib, semaxanib, axitinib, PP-121, telatinib, TSU-68. Ki8751, tivozanib, motesanib, regorafenib, vatalanib, or vandetanib.

13. The method of claim 1, wherein the PDGFR pathway inhibitor is imatinib, sunitinib, axitinib, BIBF1120, pazopanib, pnoatinib, MK-2461, dovitinib, crenolanib, PP-121, telatinib, CP 673451, TSU-68, Ki8751, tivozanib, masitinib, motesanib, MEDI-575, or regorafenib.

14. The method of claim 1, wherein the KIT pathway inhibitor is imatinib, axitinib, pazopanib, dovitinib, telatinib, Ki8751, tivozanib, masitinib, motesanib, sunitinib, 3G3, nilotinib, dasatinib, regorafenib, or vatalanib.

46. The method of claim 1 further comprising the step of determining the expression levels of VEGFR-2 in the biological sample wherein the presence of VEGFR-2 is further predictive of poor treatment outcome.

15. A method of predicting sensitivity of a cancer in a patient to VEGF/VEGFR, PDGFR, or KIT pathway inhibitors comprising:

(a) obtaining a sample of the cancer; and

(b) determining the KDR, PDGFR, and KIT level in the sample, wherein if the KDR, PDGFR, or KIT level is elevated, then the cancer is predicted to be sensitive to VEGF/VEGFR, PDGFR, or KIT pathway inhibitors.

40. A method of treating a cancer patient comprising:

(a) determining if the patient has a cancer that is sensitive to VEGF/VEGFR, PDGFR, or KIT pathway inhibitors according to claim 15; and

(b) treating the patient determined to have a cancer that is sensitive to VEGF/VEGFR, PDGFR, or KIT pathway inhibitors with VEGF/VEGFR, PDGFR, or KIT pathways inhibitors.

16-28. -28. (canceled)

29. A method of predicting sensitivity of a cancer in a patient to EGFR inhibitors or platinum-based chemotherapy comprising:

(a) obtaining a sample of the cancer; and

(b) determining the KDR level in the sample, wherein if the KDR level is not elevated, then the cancer is predicted to be sensitive to EGFR inhibitors or platinum-based chemotherapy.

30-39. -39. (canceled)

41-42. -42. (canceled)

43. A method of determining a prognosis of a cancer patient comprising:

(a) obtaining a sample of the patient'"'"'s cancer; and

(b) detecting polymorphisms at nucleotides−

37 and 1416 in the KDR gene in the cells comprising the sample, wherein the cancer is determined to have a better prognosis if the −

37 AG/GG and (or?) 1416 AT/TT polymorphisms are present.

44. A method of treating a cancer patient comprising:

(a) determining the cancer patient'"'"'s prognosis according to claim 43; and

(b) applying an aggressive anticancer therapy if the polymorphisms are absent.

45. (canceled)

47-48. -48. (canceled)