Patient-Derived Tumor Xenografts May Help to Personalize Bladder Cancer Treatment

Urology Practice Management - December 2015, Vol 4, No 6 - Bladder Cancer
Laura Morgan

In the era of personalized medicine, identifying patients with cancer who will benefit most from a specific treatment is the Holy Grail. Currently, there is no test to identify effective chemotherapy before administering treatment. Finding screening tests can improve treatment selection and improve outcomes. “By prescreening, we can determine which medication works, providing a much higher chance the patient will benefit,” said Chong-xian Pan, MD, PhD, Division of Hematol­ogy/Oncology, University of California Davis, Sacramento, in a press release from the university. “This can reduce toxicity, increase efficiency, and lower costs,” he added.

Designing patient-specific molecularly guided targeted therapy to target the genetic anomalies of the disease is gaining momentum in precision medicine. However, studies indicate that matching molecularly guided targeted therapy against patient-specific genetic mutations is associated with poor response rates, partially because most tumors involve several genetic mutations and current technologies are unable to precisely differentiate between mutations that are essential for cancer-cell growth and those that have little to no role in such function. Furthermore, current models of precision medicine, including xenografts from cultured cancer cells, have been less than successful, because they acquire additional mutations during in vitro culturing, and therefore do not match the original cancer.

Bladder Cancer

Bladder cancer is often considered to be the most understudied and underfunded cancer. Identifying therapies that will improve outcomes in patients with aggressive bladder cancer is important, because there has been no significant improvement in the overall survival and prognosis for this patient population in the past 30 years; no FDA-approved targeted therapy is available for the disease.

Unmet Needs

In an effort to fill this unmet need, a team of researchers from the University of California at Davis established 22 patient-derived xenografts for bladder cancer, using unselected and uncultured clinical patient specimens in immunodeficient mice, in hopes that the xenografts would identify the key mutations in bladder cancer that would respond to therapy (PLoS One. 2015;10:e0134346). Dr Pan and colleagues used the xenografts to determine sensitivity to cisplatin (Platinol), gemcitabine (Gemzar), and the combination of these 2 drugs, which is often used as first-line therapy for advanced bladder cancer.

The researchers found that unlike some precision medicine technologies that rarely mirror parental tumors, 92% to 97% of the genetic aberrations from the original patient cancers were maintained in the xenografts. In addition, 4 of the first 6 xenografts were sensitive to the combination of cisplatin and gemcitabine, and chemoresistance to 1 drug was overcome by the other drug, which correlates with known patient response to treatment.

The researchers noted that a unique feature of the xenograft is that many identical grafts from a specific patient can be generated, allowing researchers to screen multiple targeted therapies as well as chemotherapy (single agents or in combination) to select the most effective drug combinations.

If the patient-derived xenograft platform is validated, it can be used for several purposes, including deciphering the mechanisms of primary resistance, screening multiple therapeutic agents simultaneously to select the most effective drugs or drug combinations, and developing biomarkers for patient selection in clinical decision-making.

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Last modified: December 29, 2015
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