A NOTE ON KIDNEY CANCER

As we suggested, there is evidence that the treatment of Clear cell renal cancer should be different from that of papillary cancers.  Papillary cancers are MET driven and therefore more treatable with Sutent, Avastin, and Lapatinib.  Basically, anti-VEGF will be more likely to work because this is where MET has the strongest influence.   The Von Hippel Lindau is more associated with clear cell, and here the driving is non degradation of the Hypoxia-Inducible Factor which then dimerise to exarcebated VEGF, but have more disturbance at mitochondria.  An mTor inhibitor should be the driver Medicine.  There is VEGF amplification which is secondary.   The Hypoxia-Inducible Factor prominence in VHL brings to bear many disturbances not only in the Cytosol (on Amplification of signal transduction pathways, cyclins and growth factors), but also in the Mitochondria where Hypoxia disrupts cellular respiratory function.  Nuclear disruptions are more notable in clear cells.  The mTor inhibitors really act here more and therefore should be the main drug in the treatment of Clear cell cancer.  The Combination of these drugs appears to be a more adequate standard of care, particularly in refractory disease.

In relapse and refractory diseases, addition of Interferon which modulates the cyclins and recruist immune defense to the mix is an option.  Cytotoxics (chemotherapy drug such as Gemzar) could have a role, but not alone.  anti-VEGF and/or anti-mTor must be left in the mix/combination.

When DR Toni Choueiri was working on Cabozantinib, he included papillary and clear cell alike, and got results in both groups. Cabozantinib is an Anti- c-MET and VEGFR2.  The result of that study with a  14.7 months  progression free survival stresses the heavy participation of Angiogenesis in Kidney cancer in general, no matter the type.

While it is easy to infer that a combination of these drugs  would be the best option to achieve higher response rates, when you look at survival of the patients one is surprised sometimes when sequential administration of these therapeutic options yields equivalent survival in clinical trial.

I should remind the reader that Cabozantinib has activity in prostate Cancer (a lower dosage). And that Axitinib, another Anti-VEGF (1-3), with activity at Platelet derived Growth factor and c-KIT (CD 117) has also a role in Kidney cancer and should not be forgotten.  This drug has been combined to Gemzar in Pancreatic cancers.

Of note, "Angiogenesis genes EMCN and NOS3 and immune related genes CCL4, CXCL9" have prognosis value.  Other genes of Prognosis Value include CA9, MKI67,CD274, BIRC5 (ALSO CALLED  SURVIVIN). (Lancet Oncology pg 9).

The cure is within reach.  We work hard at the CRBCM!