Top

Published in:

Open Access 01-12-2016 | Research

Changes in plasma biomarkers following treatment with cabozantinib in metastatic castration-resistant prostate cancer: a post hoc analysis of an extension cohort of a phase II trial

Authors: Raya Leibowitz-Amit, Melania Pintilie, Leila Khoja, Arun A. Azad, Raanan Berger, A. Douglas Laird, Dana T. Aftab, Kim N. Chi, Anthony M. Joshua

Published in: Journal of Translational Medicine | Issue 1/2016

Abstract

Background

Cabozantinib is an orally available inhibitor of tyrosine kinases including VEGFR2 and c-MET. We performed a post hoc analysis to find associations between select plasma biomarkers and treatment response in patients (pts) with metastatic castration resistant prostate cancer (mCRPC) who received cabozantinib 100 mg daily as part of a phase 2 non-randomized expansion cohort (NCT00940225).

Methods

Plasma samples were collected at baseline, 6 weeks and at time of maximal response from 81 mCRPC pts with bone metastases, of which 33 also had measurable soft-tissue disease. Levels of 27 biomarkers were measured in duplicate using enzyme-linked immunosorbent assay. Spearman correlation coefficients were calculated for the association between biomarker levels or their change on treatment and either bone scan response (BSR) or soft tissue response according to RECIST.

Results

A BSR and RECIST response were seen in 66/81 pts (81 %) and 6/33 pts (18 %) respectively. No significant associations were found between any biomarker at any time point and either type of response. Plasma concentrations of VEGFA, FLT3L, c-MET, AXL, Gas6A, bone-specific alkaline phosphatase, interleukin-8 and the hypoxia markers CA9 and clusterin significantly increased during treatment with cabozantinib irrespective of response. The plasma concentrations of VEGFR2, Trap5b, Angiopoietin-2, TIMP-2 and TIE-2 significantly decreased during treatment with caboznatinib.

Conclusions

Our data did not reveal plasma biomarkers associated with response to cabozantinib. The observed alterations in several biomarkers during treatment with cabozantinib may provide insights on the effects of cabozantinib on tumor cells and on tumor micro-environment and may help point to potential co-targeting approaches.

Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011;144(5):646–74. doi:10.1016/j.cell.2011.02.013.PubMedCrossRef

Lalonde E, Ishkanian AS, Sykes J, Fraser M, Ross-Adams H, Erho N, et al. Tumour genomic and microenvironmental heterogeneity for integrated prediction of 5-year biochemical recurrence of prostate cancer: a retrospective cohort study. Lancet Oncol. 2014;15(13):1521–32. doi:10.1016/S1470-2045(14)71021-6.PubMedCrossRef

Cooke VG, LeBleu VS, Keskin D, Khan Z, O’Connell JT, Teng Y, et al. Pericyte depletion results in hypoxia-associated epithelial-to-mesenchymal transition and metastasis mediated by met signaling pathway. Cancer Cell. 2012;21(1):66–81. doi:10.1016/j.ccr.2011.11.024.PubMedPubMedCentralCrossRef

Ranasinghe WK, Xiao L, Kovac S, Chang M, Michiels C, Bolton D, et al. The role of hypoxia-inducible factor 1alpha in determining the properties of castrate-resistant prostate cancers. PLoS One. 2013;8(1):e54251. doi:10.1371/journal.pone.0054251.PubMedPubMedCentralCrossRef

Adamski JK, Estlin EJ, Makin GW. The cellular adaptations to hypoxia as novel therapeutic targets in childhood cancer. Cancer Treat Rev. 2008;34(3):231–46. doi:10.1016/j.ctrv.2007.11.005.PubMedCrossRef

McDonald PC, Winum JY, Supuran CT, Dedhar S. Recent developments in targeting carbonic anhydrase IX for cancer therapeutics. Oncotarget. 2012;3(1):84–97.PubMedPubMedCentralCrossRef

Pennacchietti S, Michieli P, Galluzzo M, Mazzone M, Giordano S, Comoglio PM. Hypoxia promotes invasive growth by transcriptional activation of the met protooncogene. Cancer Cell. 2003;3(4):347–61.PubMedCrossRef

Liu T, Mendes DE, Berkman CE. From AR to c-Met: androgen deprivation leads to a signaling pathway switch in prostate cancer cells. Int J Oncol. 2013;43(4):1125–30. doi:10.3892/ijo.2013.2020.PubMedPubMedCentral

Knudsen BS, Gmyrek GA, Inra J, Scherr DS, Vaughan ED, Nanus DM, et al. High expression of the Met receptor in prostate cancer metastasis to bone. Urology. 2002;60(6):1113–7.PubMedCrossRef

10.

Lu KV, Chang JP, Parachoniak CA, Pandika MM, Aghi MK, Meyronet D, et al. VEGF inhibits tumor cell invasion and mesenchymal transition through a MET/VEGFR2 complex. Cancer Cell. 2012;22(1):21–35. doi:10.1016/j.ccr.2012.05.037.PubMedPubMedCentralCrossRef

11.

Ryan CJ, Smith MR, de Bono JS, Molina A, Logothetis CJ, de Souza P, et al. Abiraterone in metastatic prostate cancer without previous chemotherapy. New Engl J Med. 2013;368(2):138–48. doi:10.1056/NEJMoa1209096.PubMedPubMedCentralCrossRef

12.

Smith MR, Sweeney CJ, Corn PG, Rathkopf DE, Smith DC, Hussain M, et al. Cabozantinib in chemotherapy-pretreated metastatic castration-resistant prostate cancer: results of a phase II nonrandomized expansion study. J Clin Oncol: Off J Am Soc Clin Oncol. 2014;32(30):3391–9. doi:10.1200/JCO.2013.54.5954.CrossRef

13.

Brown MS, Chu GH, Kim HJ, Allen-Auerbach M, Poon C, Bridges J, et al. Computer-aided quantitative bone scan assessment of prostate cancer treatment response. Nucl Med Commun. 2012;33(4):384–94. doi:10.1097/MNM.0b013e3283503ebf.PubMedPubMedCentralCrossRef

14.

Murukesh N, Dive C, Jayson GC. Biomarkers of angiogenesis and their role in the development of VEGF inhibitors. Br J Cancer. 2010;102(1):8–18. doi:10.1038/sj.bjc.6605483.PubMedPubMedCentralCrossRef

15.

Limaverde-Sousa G, Sternberg C, Ferreira CG. Antiangiogenesis beyond VEGF inhibition: a journey from antiangiogenic single-target to broad-spectrum agents. Cancer Treat Rev. 2014;40(4):548–57. doi:10.1016/j.ctrv.2013.11.009.PubMedCrossRef

16.

Sennino B, Ishiguro-Oonuma T, Wei Y, Naylor RM, Williamson CW, Bhagwandin V, et al. Suppression of tumor invasion and metastasis by concurrent inhibition of c-Met and VEGF signaling in pancreatic neuroendocrine tumors. Cancer Discov. 2012;2(3):270–87. doi:10.1158/2159-8290.CD-11-0240.PubMedPubMedCentralCrossRef

17.

You WK, Sennino B, Williamson CW, Falcon B, Hashizume H, Yao LC, et al. VEGF and c-Met blockade amplify angiogenesis inhibition in pancreatic islet cancer. Cancer Res. 2011;71(14):4758–68. doi:10.1158/0008-5472.CAN-10-2527.PubMedPubMedCentralCrossRef

18.

Yakes FM, Chen J, Tan J, Yamaguchi K, Shi Y, Yu P, et al. Cabozantinib (XL184), a novel MET and VEGFR2 inhibitor, simultaneously suppresses metastasis, angiogenesis, and tumor growth. Mol Cancer Ther. 2011;10(12):2298–308. doi:10.1158/1535-7163.MCT-11-0264.PubMedCrossRef

19.

DePrimo S, Wu B, Huang S, Bautista R, Cancilla B, Vysotskaia V, et al. Correlative tumor molecular profiling and plasma biomarker analysis in a phase II study of XL184 in patients with progressive or recurrent glioblastoma multiforme (GBM). ASCO Meet Abstr. 2009;27(15S):2049.

20.

Corn PG, Varkaris A, Li N, Tapia EM, Araujo JC, Aparicio A, Tu SM, et al. Modulation of soluble c-Met, bone turnover markers, angiogenic factors, and c-Met in men with mCRPC treated with cabozantinib. ASCO Meet Abstr. 2013;31(6_suppl):58.

21.

Jahangiri A, Aghi MK, Carbonell WS. Beta1 integrin: critical path to antiangiogenic therapy resistance and beyond. Cancer Res. 2014;74(1):3–7.PubMedPubMedCentralCrossRef

22.

Bentzien F, Zuzow M, Heald N, Gibson A, Shi Y, Goon L et al. In vitro and in vivo activity of cabozantinib (XL184), an inhibitor of RET, MET, and VEGFR2, in a model of medullary thyroid cancer. Thyroid. 2013;23(12):1569–77.PubMedPubMedCentralCrossRef

23.

Li C, Wu JJ, Hynes M, Dosch J, Sarkar B, Welling TH et al. c-Met is a marker of pancreatic cancer stem cells and therapeutic target. Gastroenterology. 2011;141(6):2218-27 e5.PubMedCrossRef

24.

Navis AC, Bourgonje A, Wesseling P, Wright A, Hendriks W, Verrijp K, et al. Effects of dual targeting of tumor cells and stroma in human glioblastoma xenografts with a tyrosine kinase inhibitor against c-MET and VEGFR2. PLoS One. 2013;8(3):e58262. doi:10.1371/journal.pone.0058262.PubMedPubMedCentralCrossRef

25.

Müller T, DePrimo S, McGrath G, Yu P, Wu J, Goon L, et al. Abstract B269: Pharmacodynamic and correlative biomarker analyses in clinical trials of XL184, an oral, potent inhibitor of MET, VEGFR2, and RET. Mol Cancer Ther. 2009;8(12 Supplement):B269. doi:10.1158/1535-7163.targ-09-b269.CrossRef

26.

Varkaris A, Corn PG, Efstathiou E, Parikh NU, Song JH, Hoang AG et al. Integration of murine and clinical trials links modulation of the tumor-associated microenvironment to cabozantinib efficacy in mCRPC, Abstract, Prostate Cancer Foundation Scientific Retreat. 2013. http://www.pcf.org/atf/cf/{7c77d6a2-5859-4d60-af47-132fd0f85892}/Andreas_Varkaris.pdf

27.

Lin H, Jiang X, Zhu H, Jiang W, Dong X, Qiao H, et al. 2ME2 inhibits the activated hypoxia-inducible pathways by cabozantinib and enhances its efficacy against medullary thyroid carcinoma. Tumour Biol. 2015;. doi:10.1007/s13277-015-3816-1.

28.

Grullich C. Cabozantinib: a MET, RET, and VEGFR2 tyrosine kinase inhibitor. Recent results in cancer research Fortschritte der Krebsforschung Progres dans les recherches sur le cancer. 2014;201:207–14. doi:10.1007/978-3-642-54490-3_12.PubMed

29.

Shiozawa Y, Pedersen EA, Patel LR, Ziegler AM, Havens AM, Jung Y, et al. GAS6/AXL axis regulates prostate cancer invasion, proliferation, and survival in the bone marrow niche. Neoplasia. 2010;12(2):116–27.PubMedPubMedCentralCrossRef

30.

Mishra A, Wang J, Shiozawa Y, McGee S, Kim J, Jung Y, et al. Hypoxia stabilizes GAS6/Axl signaling in metastatic prostate cancer. Mol Cancer Res MCR. 2012;10(6):703–12. doi:10.1158/1541-7786.MCR-11-0569.PubMedCrossRef

31.

Eisen T, Joensuu H, Nathan PD, Harper PG, Wojtukiewicz MZ, Nicholson S, et al. Regorafenib for patients with previously untreated metastatic or unresectable renal-cell carcinoma: a single-group phase 2 trial. Lancet Oncol. 2012;13(10):1055–62. doi:10.1016/S1470-2045(12)70364-9.PubMedCrossRef

32.

Smith MR, De Bono JS, Sternberg CN, Le Moulec S, Oudard S, De Giorgi U et al. Final analysis of COMET-1: Cabozantinib (Cabo) versus prednisone (Pred) in metastatic castration-resistant prostate cancer (mCRPC) patients (pts) previously treated with docetaxel (D) and abiraterone (A) and/or enzalutamide (E). ASCO Meet Abstr. 2015;33(7_suppl):139.

33.

Basch EM, Scholz MC, De Bono JS, Vogelzang NJ, De Souza PL, Marx GM et al. Final analysis of COMET-2: Cabozantinib (Cabo) versus mitoxantrone/prednisone (MP) in metastatic castration-resistant prostate cancer (mCRPC) patients (pts) with moderate to severe pain who were previously treated with docetaxel (D) and abiraterone (A) and/or enzalutamide (E). ASCO Meet Abstr. 2015;33(7_suppl):141.

34.

Fiaschi T, Giannoni E, Taddei ML, Cirri P, Marini A, Pintus G, et al. Carbonic anhydrase IX from cancer-associated fibroblasts drives epithelial-mesenchymal transition in prostate carcinoma cells. Cell Cycle. 2013;12(11):1791–801. doi:10.4161/cc.24902.PubMedPubMedCentralCrossRef

35.

Kalin M, Cima I, Schiess R, Fankhauser N, Powles T, Wild P, et al. Novel prognostic markers in the serum of patients with castration-resistant prostate cancer derived from quantitative analysis of the pten conditional knockout mouse proteome. Eur Urol. 2011;60(6):1235–43. doi:10.1016/j.eururo.2011.06.038.PubMedCrossRef

36.

Escaff S, Fernandez JM, Gonzalez LO, Suarez A, Gonzalez-Reyes S, Gonzalez JM, et al. Study of matrix metalloproteinases and their inhibitors in prostate cancer. Br J Cancer. 2010;102(5):922–9. doi:10.1038/sj.bjc.6605569.PubMedPubMedCentralCrossRef

37.

Fiaschi T, Marini A, Giannoni E, Taddei ML, Gandellini P, De Donatis A, et al. Reciprocal metabolic reprogramming through lactate shuttle coordinately influences tumor-stroma interplay. Cancer Res. 2012;72(19):5130–40. doi:10.1158/0008-5472.CAN-12-1949.PubMedCrossRef

38.

Codony-Servat J, Marin-Aguilera M, Visa L, Garcia-Albeniz X, Pineda E, Fernandez PL, et al. Nuclear factor-kappa B and interleukin-6 related docetaxel resistance in castration-resistant prostate cancer. Prostate. 2013;73(5):512–21. doi:10.1002/pros.22591.PubMedCrossRef

39.

Herman JG, Meadows GG. Increased class 3 semaphorin expression modulates the invasive and adhesive properties of prostate cancer cells. Int J Oncol. 2007;30(5):1231–8.PubMed

40.

Sharma J, Gray KP, Harshman LC, Evan C, Nakabayashi M, Fichorova R, et al. Elevated IL-8, TNF-alpha, and MCP-1 in men with metastatic prostate cancer starting androgen-deprivation therapy (ADT) are associated with shorter time to castration-resistance and overall survival. Prostate. 2014;74(8):820–8. doi:10.1002/pros.22788.PubMedCrossRef

41.

Culig Z. CXCL8, an underestimated “bad guy” in prostate cancer. Eur Urol. 2013;64(2):189–90. doi:10.1016/j.eururo.2012.09.024 (discussion 90-2).PubMedCrossRef

42.

Koltai T. Clusterin: a key player in cancer chemoresistance and its inhibition. OncoTargets Ther. 2014;7:447–56. doi:10.2147/OTT.S58622.CrossRef

43.

Hegele A, Wahl HG, Varga Z, Sevinc S, Koliva L, Schrader AJ, et al. Biochemical markers of bone turnover in patients with localized and metastasized prostate cancer. BJU Int. 2007;99(2):330–4. doi:10.1111/j.1464-410X.2006.06604.x.PubMedCrossRef

44.

Miyata Y, Sakai H. Thrombospondin-1 in urological cancer: pathological role, clinical significance, and therapeutic prospects. Int J Mol Sci. 2013;14(6):12249–72. doi:10.3390/ijms140612249.PubMedPubMedCentralCrossRef

45.

Nassar ZD, Hill MM, Parton RG, Parat MO. Caveola-forming proteins caveolin-1 and PTRF in prostate cancer. Nature Rev Urol. 2013;10(9):529–36. doi:10.1038/nrurol.2013.168.

46.

Vidal SJ, Rodriguez-Bravo V, Quinn SA, Rodriguez-Barrueco R, Lujambio A, Williams E, et al. A targetable GATA2-IGF2 axis confers aggressiveness in lethal prostate cancer. Cancer Cell. 2015;27(2):223–39. doi:10.1016/j.ccell.2014.11.013.PubMedPubMedCentralCrossRef

47.

Heidegger I, Kern J, Ofer P, Klocker H, Massoner P. Oncogenic functions of IGF1R and INSR in prostate cancer include enhanced tumor growth, cell migration and angiogenesis. Oncotarget. 2014;5(9):2723–35.PubMedPubMedCentralCrossRef

48.

Lind AJ, Wikstrom P, Granfors T, Egevad L, Stattin P, Bergh A. Angiopoietin 2 expression is related to histological grade, vascular density, metastases, and outcome in prostate cancer. Prostate. 2005;62(4):394–9. doi:10.1002/pros.20163.PubMedCrossRef

49.

Thoms JW, Dal Pra A, Anborgh PH, Christensen E, Fleshner N, Menard C, et al. Plasma osteopontin as a biomarker of prostate cancer aggression: relationship to risk category and treatment response. Br J Cancer. 2012;107(5):840–6. doi:10.1038/bjc.2012.345.PubMedPubMedCentralCrossRef

50.

Doran MG, Spratt DE, Wongvipat J, Ulmert D, Carver BS, Sawyers CL, Evans MJ. Cabozantinib resolves bone scans in tumor-naïve mice harboring skeletal metastasis. Mol Imaging. 2014;13:1–5. doi:10.2310/7290.2014.00026.

Title: Changes in plasma biomarkers following treatment with cabozantinib in metastatic castration-resistant prostate cancer: a post hoc analysis of an extension cohort of a phase II trial
Authors: Raya Leibowitz-Amit
Melania Pintilie
Leila Khoja
Arun A. Azad
Raanan Berger
A. Douglas Laird
Dana T. Aftab
Kim N. Chi
Anthony M. Joshua
Publication date: 01-12-2016
Publisher: BioMed Central
Published in: Journal of Translational Medicine / Issue 1/2016
Electronic ISSN: 1479-5876
DOI: https://doi.org/10.1186/s12967-015-0747-y

Live Webinar | 27-06-2024 | 18:00 (CEST)

Keynote webinar | Spotlight on medication adherence

Reserve your place

Live: Thursday 27th June 2024, 18:00-19:30 (CEST)

WHO estimates that half of all patients worldwide are non-adherent to their prescribed medication. The consequences of poor adherence can be catastrophic, on both the individual and population level.

Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.

Prof. Kevin Dolgin

Prof. Florian Limbourg

Prof. Anoop Chauhan

Developed by: Springer Medicine

Obesity Clinical Trial Summary

At a glance: The STEP trials

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.

Developed by: Springer Medicine

Highlights from the ACC 2024 Congress

Year in Review: Pediatric cardiology

Pediatric Cardiology Video

Watch Dr. Anne Marie Valente present the last year's highlights in pediatric and congenital heart disease in the official ACC.24 Year in Review session.

Year in Review: Pulmonary vascular disease

Cardiopulmonary Comorbidity Video

The last year's highlights in pulmonary vascular disease are presented by Dr. Jane Leopold in this official video from ACC.24.

Year in Review: Valvular heart disease

Valvular Heart Disease Video

Watch Prof. William Zoghbi present the last year's highlights in valvular heart disease from the official ACC.24 Year in Review session.

Year in Review: Heart failure and cardiomyopathies

Heart Failure Video

Watch this official video from ACC.24. Dr. Biykem Bozkurt discusses last year's major advances in heart failure and cardiomyopathies.

ACC 2024 Congress Coverage

Year in Review: Heart failure and cardiomyopathies

Heart Failure Video

Watch this official video from ACC.24. Dr. Biykem Bozkurt discusses last year's major advances in heart failure and cardiomyopathies.

Watch now

Semaglutide benefits people with type 2 diabetes and obesity-related heart failure

16-04-2024 Type 2 Diabetes News

Incentivised to exercise

11-04-2024 Lifestyle Modifications News

New intervention for STEMI-related cardiogenic shock

10-04-2024 Myocardial Infarction News

» View more highlights on the ACC 2024 congress hub page

Image Credits

Illustration of figure on mountain summit/© Orapun / Stock.adobe.com, STEP AAG HeroTeaserCollection image/© Tarek / Generated with AI / Stock.adobe.com, ACC 2024 Pediatric and Congenital Heart Disease: Year in Review/© 2024 American College of Cardiology, ACC 2024 Pulmonary Vascular Disease: Year in Review/© 2024 American College of Cardiology, ACC 2024 Valvular Heart Disease: Year in Review/© 2024 American College of Cardiology, ACC 2024 HF and Cardiomyopathies: Year in Review/© 2024 American College of Cardiology, Woman out walking/© Seventyfour / stock.adobe.com (symbolic image with model), Woman checking smartwatch /© saltdium / stock.adobe.com (symbolic image with model), Cardiac catheterization/© Damian / stock.adobe.com

At a glance: The STEP trials

Springer Medicine

Abstract

Background

Methods

Results

Conclusions

Please log in to get access to this content

Other articles of this Issue 1/2016

Insulin-like growth factor-1 deficiency and metabolic syndrome

Is chronic fatigue syndrome truly associated with haplogroups or mtDNA single nucleotide polymorphisms?

Ion channels expression and function are strongly modified in solid tumors and vascular malformations

Next-generation sequencing in thyroid cancer

Rapid reconstitution of CD4 T cells and NK cells protects against CMV-reactivation after allogeneic stem cell transplantation

Guizhi-Shaoyao-Zhimu decoction attenuates rheumatoid arthritis partially by reversing inflammation-immune system imbalance

Live: Thursday 27th June 2024, 18:00-19:30 (CEST)

Highlights from the ACC 2024 Congress

ACC 2024 Congress Coverage