John Ebos of Roswell Park Cancer Institute was granted a Career Development Award by the Congressionally Directed Medical Research Programs of the Department of Defense (DoD) to study, using a pre-clinical model, rebound and resistance to targeted therapies in RCC. This two-year grant was funded at $602,996 in Fiscal Year 2013 (the latest award year).

This project is designed to answer a number of important questions, in regard to targeted therapy, that have not been adequately addressed heretofore.

• What happens when there is a cessation of targeted therapy? Does the cancer rebound and grow or is there quiescence?
• What biological mechanism causes resistance to targeted therapy? We know that the best of the targeted therapies, sunitinib (Sutent), has, according to the seminal Phase III trial results, a progression-free survival of around 11 months (sunitinib will be the agent that will be used in Dr. Ebos’ study).
• We know that tumor cells circulate in the bloodstream, but to be designated as a metastasis, they have to alight in some tissue somewhere – in the lung, liver, bones, etc. The spot where they settle and interact with the surrounding tissue, or stroma, is called the microenvironment. If this microenvironment were not hospitable to the tumor cells, there would be no metastatic growth. But what is it about the biological make-up of the stroma that allows it to accept and even support the metastasis? Is there something about the stroma itself that invites the tumor cells, or has the stroma itself been modified to accept the cells? Do the tumor cells and stroma cells have the same genetic aberrations? John Ebos will investigate these issues.
• At which stage does an anti-angiogenic drug work best, pre- (neoadjuvant ) or post surgically? Does it better target the primary tumor or should it be used to address metastasis? Certain drugs that could be overlooked may not affect the primary tumor but could have a profound effect in preventing the spread of the disease.

If the drug companies, in the case of sunitinib, Pfizer, knew the answers to the above questions, they could develop combination therapies to counteract any rebound growth or resistance and thereby extend the period before tumor progression recurs, and, in so doing, extend the survival time of the patient. As a follow-up to the project, John Ebos’ team will investigate molecules that could be combined with targeted therapy to increase its efficacy.

But before we get ahead of the game, this study is pre-clinical, that is, its subjects are mice, not humans. Nevertheless, one of John Ebos’ objectives is to develop a mouse model that recapitulates the cancer experience of humans. First, a human renal cell carcinoma (RCC) is implanted into the mouse kidney (note that scientists have not been able to induce RCC in a mouse so must implant a humor tumor in a mouse and then observe the effects). The human RCC tissue will have been pre-selected to be highly aggressive disease that would hopefully cause a metastatic response in the mouse. Waiting a while after implantation, the team will perform a nephrectomy on the mouse and await any metastasis. If found, the tumor cells will be resected and re-implanted in treatment-naïve mice in order to enhance the metastatic population. These mice will then be treated with sunitinib.

Let’s assume that there is resistance to sunitinib, then there is a break in the treatment, then sunitinib is re-applied? We know that, in humans, when the same therapy is re-administered after initial progression and therapy cessation, it is found that the therapy may again prove to be effective, albeit to a lesser extent. The questions we have are: what genetic modifications caused the resistance in the first place, then what other changes in the microenvironment allowed re-introduction of the therapy to cause a lower but real response in the tumor cells the second time around?

Editor’s Comment

We have always felt that kidney cancer will only be successfully attacked by a combination of therapies, as the AIDS virus has been dealt with. The new, “hottest” drugs are the anti-PD-1 immunotherapies, which are developed to lower the resistance to the body’s own immune system (killer T-cells), which would normally fight the “foreign” tumor cells. The targeted, anti-angiogenic drugs are designed to attack the tumor’s infrastructure, i.e., the vasculature that brings nutrients to the quickly expanding and proliferating cancer cells. Could we see, in the future, a combination of anti-PD-1 therapy, a targeted therapy, and a molecule that overcomes the inevitable resistance to the targeted therapy – all of which would completely knock out the metastasis? Let the research begin!