There are 338,000 new cases of kidney cancer per year worldwide, and the incidence has increased in recent years (Ferley et al., 2012). Although the majority of Renal Cell Carcinoma (RCC) cases are sporadic and affect those over 50 years old, 2-3% of cases are caused by inherited conditions such as BHD, VHL, HLRCC and TSC and are associated with an earlier onset (Randall et al., 2014). These inherited forms of RCC have provided great insights into the genetics of sporadic cancer – for example 75% of RCC cases are associated with mutations in the VHL gene.
The majority of small local RCC tumours can be surgically removal. However these treatments are not without risk and complete nephrectomies leave patients with severely reduced kidney function. The development of selective drug treatments that target only cancerous cells could therefore increase patient quality of life.
Current treatments for advanced or metastasised RCC are focused on counteracting the metabolic and angiogenic changes associated with the VHL/HIF pathway: Tyrosine Kinase Inhibitors (TKI) sunitinib, sorafenib and axitinib inhibit VEGF and PDGF signalling, increased as a result of aberrant HIF signalling, to limit angiogenesis; and the mTOR inhibitor everolimus, and derivatives, reduce mTOR and downstream HIF signalling to minimise tumour growth and the metabolic shift from oxidative phosphorylation to glycolysis. Despite these advances only half of kidney cancer patients are currently expected to survive past 10 years (Chow et al., 2010), so more advanced and effective treatments are sorely required.
This week’s blog is a brief review of several recent reports on the development of new treatments for RCC and updates on current treatments.
- Englerin A, a purified molecule from Phyllanthus engleri bark, selectively kills cancer cells (Ratnayake et al., 2009) by increasing intracellular calcium levels (Sulzmaier et al., (2012). Akbulut et al., (2015) now report that activation of the Transient Receptor Potential cation channels TRPC4 and TRPC5 induces calcium influx resulting in rapid death of tumourigenic cells, thereby identifying novel drug targets for the selectively treatment of cancerous kidney cells.
- Hall et al., (2014) reported that TRPM3 cation channel activation promotes clear cell RCC tumour growth by activating autophagy. Increased intracellular calcium levels remove miR-214-inhibition of autophagy, however this pathway can be blocked by mefenamic acid (MFA). The identified drug targets could form the basis of an effective combination treatment targeting the upregulation of autophagy and tumourigenic angiogenesis.
- Additional targets identified through genetic and biochemical studies of tumours and tumour cell lines include HIF2α, chromatin regulators SETD2, BAP1 and PBRM, MET in papillary type I tumours, and inhibitors that can limit glucose uptake in tumours that have switched to aerobic glycolysis as the main source of energy (reviewed in Srinivasan et al., 2015).
In addition to this new research, preliminary data from several clinical trials has recently been released.
- A trial assessing a combination of dalantercept and axitinib for treatment of advanced RCC reported encouraging results. In part 1 of the phase II trial dalantercept, and ALK-1 inhibitor, in combination with the multiple TKI axitinib, showed a partial response and prolonged disease control in patients. A larger phase II part 2 trial will assess if the combination therapy enhances progression free survival more than treatment with axitinib alone.
- The ASSURE clinical trial reported that adjuvant use of sorafenib and sunitinib did not significant improve disease free survival or overall survival, nor reduction time to disease recurrence compared to a placebo in patients following surgical tumour removal. Due to significant side effects both drugs were individually titrated to reduce the high discontinuation rate.
- Phase II trial results results show lenvatinib, a multi-TKI, alone or in combination with everolimus, prolongs progression free survival significantly more than everolimus treatment alone in patients with advanced or metastatic RCC. The combination therapy inhibits multiple tumourigenic signalling pathways simultaneously reducing the risk of developed drug resistance.
- A combinatorial trial of Bevacizumab and Erlotinib in HLRCC and sporadic papillary RCC patients reported a 65% and 29% response rate in HLRCC patients and sporadic patients respectively, with the majority of tumours shrinking or remaining stable and extended survival. The enhanced need of these papillary tumours for high levels of glucose makes them particularly susceptible to treatments that impair glucose delivery.
As RCC is really a collection of distinct diseases that occur in the same organ, it is unlikely that any one single therapy will be suitable for all patients. Instead through increased understanding of the tumourigenic pathways and processes in different patient cohorts more personalised targeted therapies (as discussion in this blog post) can be developed.
- Akbulut Y, Gaunt HJ, Muraki K, Ludlow MJ, Amer MS, Bruns A, Vasudev NS, Radtke L, Willot M, Hahn S, Seitz T, Ziegler S, Christmann M, Beech DJ, Waldmann H. (-)-Englerin A is a Potent and Selective Activator of TRPC4 and TRPC5 Calcium Channels. Angew Chem Int Ed Engl. 2015 Mar 16;54(12):3787-91. PubMed PMID: 25707820.
- Chow WH, Dong LM, Devesa SS. Epidemiology and risk factors for kidney cancer. Nat Rev Urol. 2010 May;7(5):245-57. Review. PubMed PMID: 20448658.
- Ferlay J, Soerjomataram I, Ervik M, et al. GLOBOCAN 2012 v1.0, Cancer Incidence and Mortality Worldwide: IARC CancerBase No. 11 [Internet]. Lyon, France: International Agency for Research on Cancer; 2013. Available from:http://globocan.iarc.fr, accessed March 2015.
- Hall DP, Cost NG, Hegde S, Kellner E, Mikhaylova O, Stratton Y, Ehmer B, Abplanalp WA, Pandey R, Biesiada J, Harteneck C, Plas DR, Meller J, Czyzyk-Krzeska MF. TRPM3 and miR-204 establish a regulatory circuit that controls oncogenic autophagy in clear cell renal cell carcinoma. Cancer Cell. 2014 Nov 10;26(5):738-53. PubMed PMID: 25517751.
- Randall JM, Millard F, & Kurzrock R (2014). Molecular aberrations, targeted therapy, and renal cell carcinoma: current state-of-the-art. Cancer metastasis reviews, 33 (4), 1109-24 PMID: 25365943
- Ratnayake R, Covell D, Ransom TT, Gustafson KR, Beutler JA. Englerin A, a selective inhibitor of renal cancer cell growth, from Phyllanthus engleri. Org Lett. 2009 Jan 1;11(1):57-60. PubMed PMID: 19061394.
- Srinivasan R, Ricketts CJ, Sourbier C, Linehan WM. New strategies in renal cell carcinoma: targeting the genetic and metabolic basis of disease. Clin Cancer Res. 2015 Jan 1;21(1):10-7. PubMed PMID:25564569.
- Sulzmaier FJ, Li Z, Nakashige ML, Fash DM, Chain WJ, Ramos JW. Englerin a selectively induces necrosis in human renal cancer cells. PLoS One. 2012;7(10):e48032. PubMed PMID: 23144724.