RCC metastasizes easily, often spreading to the lungs and other organs. In cases where metastatic disease is not yet present at time of diagnosis, the five-year survival rate for RCC patients is approximately sixty to seventy-five percent (60-75%). However, metastasis is already present at diagnosis in approximately one-third of RCC cases. In cases where the tumor has metastasized to the lymph nodes, the five-year survival rate is reduced to five to fifteen percent (5-15%). In cases where the cancer has spread to other organs, the five-year survival rate is less than five percent (5%).

RCC responds poorly to chemotherapy and radiation therapy. Cytotoxic chemotherapy, an integral therapeutic component for solid and non-solid tumors, shows little or no anti-tumor activity against RCC. Complete eradication of RCC by chemotherapy is therefore unlikely, unless all of the cancer can be removed by surgery. Radiation therapy is usually unsuccessful in treating RCC and is therefore not commonly used. In light of the fact that chemotherapy and radiation therapy mediate their anti-tumor effects by inducing apoptosis, poor response of RCC to these conventional therapies has been hypothesized to associate with the signal transduction pathway that mediates apoptosis in RCC.

INNOVATION:  Researchers at UCLA have identified the proapoptotic protein Smac/DIABLO as a gene product with significant prognostic and therapeutic value for RCC.

It has been shown that expression level, transcription regulation, and biological activity of Smac/DIABLO determine in large part the pathogenesis of RCC and the response of RCC to anti-tumor therapies and agents, including chemotherapy, irradiation, immunotherapy, gene therapy, toxins and antibodies. Smac/DIABLO offers promising utility as a prognostic biomarker for RCC.

It has been shown also that the resistance of tumor cells to apoptotic stimuli is due in part to low expression of Smac/DIABLO. Furthermore, upregulation of Smac/DIABLO by certain drugs is known to sensitize cells to apoptosis. Aside from the role of Smac/DIABLO in the regulation of apoptotic activity, it is posited that activation of Smac/DIABLO expression is important in reversing RCC resistance to chemotherapy, irradiation, and immunotherapy.

POTENTIAL APPLICATIONS 

PROGNOSTIC APPLICATIONS:  Use of Smac/DIABLO as a prognostic biomarker will focus on the relative expression levels of Smac/DIABLO in cancerous tissue cells of the RCC patient, as compared to measured expression levels in autologous normal kidney tissue, or to normal expression levels of control tissue. Detection and quantification of Smac/DIABLO activity (i.e., protein transcription and expression) in cancerous tissue following biopsy or surgery may be accomplished through immunohistochemistry, RT-PCR, Western blot analysis, flow cytometry, and/or HPLC. Low or negative expression of Smac/DIABLO will generally indicate a poor prognosis. On the other hand, poor expression will also suggest a choice of therapy, which either may be independent of, or may involve the use of agents to upregulate, Smac/DIABLO expression.

THERAPEUTIC APPLICATIONS:  Analysis of Smac/DIABLO expression will be of significant clinical importance in the design of therapeutic strategies. Smac/DIABLO expression can be induced by use of agents that sensitize cells to apoptosis (e.g., chemicals, inhibitors, biologicals, antisense RNA, gene transfection reagents). An alternative strategy would be to use protease inhibitors to prevent degradation of Smac/DIABLO. Enhanced expression or reduced degradation resulting therefrom may then cause the spontaneous induction of apoptosis, or may be used synergistically in combination with low-dose chemotherapy, radiation, or immunotherapy.

INVENTOR:  Dr. Benjamin Bonavida is a Professor in the Department of Microbiology, Immunology and Molecular Genetics at UCLA's David Geffen School of Medicine, and is a Member of the Tumor Immunology Research Group at UCLA's Jonsson Comprehensive Cancer Center.

Reference: UCLA Case No. 2005-017

PCT Publication Number: PCT/US05/041896