The Keystone Program in Personalized Kidney Cancer Therapy

The Potential

“This program could easily achieve ‘Top 5’ status. Most other kidney cancer programs in the country either lack this scientific depth and/or lack sufficient clinical expertise.” – Keystone Programs External Review Panel

Current Projects

The Keystone Program in Personalized Kidney Cancer Therapy was established in 2008. Since then, the program has made a significant investment to improve and expand its Kidney Cancer Database. A shared resource for all investigators, the database now includes outcome data from more than 2,000 patients. The Fox Chase Cancer Center Biosample Repository contains 883 blood samples and 952 staged tumor specimens matched to patients who have kidney cancer. The database also features a tissue microarray showing changing patterns of gene activity in primary kidney tumors, lymph nodes and metastatic tumors.

In addition, Keystone Program funds have been used to support 10 pilot research projects, recruit a new research scientist and establish a visiting scientist program. Clinicians and scientists meet monthly to present progress reports and develop ideas for new research collaborations.

The researchers form interdisciplinary teams that work together to answer fundamental scientific questions. Based on their research findings, Keystone Program leaders then select the most promising pilot studies for additional funding. Current questions being studied include:

1. How does the human immune system respond to renal cell cancer?
• Using data from the Kidney Cancer Database, Keystone researchers found that RCC patients with a low white blood cell count were more likely to have advanced tumors and a poor prognosis. Researchers now are studying whether tumor progression is linked to the relative numbers of specific types of immune cells.


2. How can we identify aggressive renal cell tumors earlier?
• Keystone researchers are analyzing tumor specimens to identify a biochemical "signature" for aggressive forms of renal cell carcinoma. They have discovered different patterns of gene expression that appear to be linked to tumor grade, stage and response to suntinib, a drug used to treat RCC.


3. Do RCC proteins have a specific signaling pattern?
• A complicated network of gene activity, enzymes and biochemical signals controls when and how proteins bind to other proteins. Keystone scientists are analyzing how changes in one important signaling pathway affect the ability of proteins in RCC cells to interact and whether these changes make tumor cells resistant to therapeutic drugs.


4. How do stromal cells affect the development of RCC?
• Keystone researchers have developed a 3D culture system to study the development of supporting cells called kidney stromal cells. So far, scientists have discovered that stromal cells develop abnormally when they are next to RCC cells in ways that could allow tumors to invade healthy kidney tissue.


5. Do patients with early-stage RCC have different amino acids in their blood serum?
• When blood samples from 47 patients with advanced RCC were compared to samples from people without RCC, Keystone scientists found significant differences in seven amino acid metabolites. The researchers are expanding this pilot study to include patients with early-stage RCC and will look for the metabolite signature in urine.


6. How are copy number abnormalities linked to RCC?
• Keystone scientists have found that cells from RCC tumors often contain abnormalities in the number of genes and chromosomes. Sometimes certain segments of DNA are absent; sometimes DNA segments are duplicated. Copy number abnormalities affect gene activity in ways that can lead to the development of cancer.

In addition, Keystone research teams are in the early stages of developing more effective treatments for RCC, including:

1. Immunoliposomes
• Membrane-covered spheres filled with anti-tumor agents that can bind to specific receptors on RCC cells and kill the cell from the inside out.


2. Enhanced interferon
• Modifying an existing cancer drug to make it more effective with fewer toxic side-effects.


3. Combination therapies and drug-like molecules
• Inhibit the spread of RCC cells