Action to Cure Kidney Cancer

Amato GiacciaAction to Cure Kidney Cancer (ACKC) is pleased to announce the awarding of a grant of $45,000 to Dr. Amato Giaccia of Stanford University to fund a research in kidney cancer. We are able to make this grant as the result of a very generous contribution to ACKC by the Cecile and Ken Youner Fund for Cancer Research, which was established in memory of Cecile Youner, the beloved wife of ACKC's Medical Director.

Dr. Giaccia is conducting research in kidney cancer that has the clear cell pathology, which represents over three-quarters of the kidney cancers. 80-85% of clear cell patients have a mutation or inactivation of the VHL gene. Given this fact, although many cancers share genes that are mutated, kidney cancer is the only cancer that has the VHL gene mutated. Therefore, cells that have inactivated VHL genes present a desirable target for therapy. VHL is a tumor suppressor gene so that when it is mutated it loses its ability to control the behavior of related genes and proteins, which consequently run amok and give rise to the kidney cancer malignancy. This paradigm would presumably make VHL an optimal target for therapy, however, tumor suppressor genes are elusive targets because it is much easier to inhibit the activity of a gene, e.g. an oncogene that cause cancer, than to pharmacologically restore the functionality of a gene. With this in mind, Dr. Giaccia drew upon the principles of "synthetic lethality", taken from classical genetics, where a gene mutation alone has no effect on the viability of the cell but the combination of the mutation and a drug (the synthesis or coming together of the two) cause the cell's, or tumor's, death.

Dr. Giaccia's lab screened 64,000 compounds against human kidney cancer cells and found three compounds that demonstrated toxicity to the cells (cytotoxicity) that were missing VHL functionality both in cell culture as well in transplanted tumors. The compounds have also shown not to be toxic to normal cells, a second requirement for synthetic lethality.

Dr. Giaccia's lab has done additional work on the mechanism of action of the compounds. The first one is identified as STF-62247 (these molecules, and their analogs, are identified by a series of numbers, in this case starting with a ‘6', for the second molecule starting with a ‘3', and for the third with a ‘5'. So the lab refers to them as 6-series, 3-series, and 5-series). The 6-series induces cell death in VHL inactivated cells by autophagy. Autophagy is a natural process whereby the cell "eats up" worn out components of the cell to reuse or excrete them. However, the 6-series molecule dysregulates this process creating a monster pacman eating up the VHL mutated cells but leaving the normal cells alone. A published paper on this research can be found in "Cancer Cell" at http://tinyurl.com/mf8baf. They are currently characterizing the 3' and 5' series compounds.

The 6-series, 3-series, and 5-series molecules are cytotoxic - they kill tumor cells. The drugs that have been introduced by Big Pharma to fight kidney cancer in the last few years such as Sutent, Nexavar, and Avastin are cytostatic agents whose objective is to disrupt the support structure of the cell to impede its growth and proliferation. For example, anti-angiogenic agents prevent formation of new blood vessels, which tumors need to grow. However, these so-called targeted therapies have had limited success, either shrinking or stabilizing the tumor for 8-12 months before it finds another way to start growing again and requiring the patient to switch to another agent. If Dr. Giaccia's molecules are shown to be effective and non-toxic in human trials, there may come a day when combining one of his cytotoxic molecules with an anti-angiogenic agent will produce a killer drug that will produce a cure rate for clear cell carcinoma. We wish him well in his endeavor.