Biomarkers of Therapeutic Response and Resistance to Androgen Receptor Signaling Inhibitors

About Biomarkers of Therapeutic Response and Resistance to Androgen Receptor Signaling Inhibitors

As their name implies, circulating tumor cells (CTCs) are cancer cells that have sloughed off tumors and entered the blood stream. Recent technological advances have made it possible to capture these rare CTCs from a simple blood draw from a patient with the hope they can be used as a “liquid biopsy” of the patient’s cancer. Dr. Lang and colleagues have developed a system of CTC capture and subsequent analysis that is so sensitive it is able to isolate one CTC out of 20 million blood cells. Their device/technology platform is called VERSA, for Vertical Exclusion-based Rare Sample Analysis. The VERSA platform vastly improves upon other CTC capture methods previously developed, acting as a version 4.0 of CTC capture. VERSA not only allows for enumeration of how many CTCs are circulating in a patient’s blood stream, which can be a marker for metastatic disease progression or spread throughout the body, it can also perform multiple functions that enable doctors to better understand an individual patient’s cancer type and tailor medications and dosages that are most likely to help that patient.

For example, from a single blood draw, VERSA can analyze one CTC to determine the exact mutations in that cancer cell and compare those mutations to another CTC from the same patient. If drugs are available that target the mutations found, doctors can identify the drug or drug combination most likely to benefit each patient. In addition, because CTCs are far more easy—not to mention less painful—to extract from a patient with metastatic cancer, than performing bone biopsies, serial analysis of a patient’s CTCs can readily be performed to determine if additional mutations are acquired during disease progression, and if so, drug therapy can be altered accordingly. In addition, VERSA can determine in real-time how well a patient is responding to a given drug or therapy and treatment can be altered rapidly to minimize patient discomfort and maximize patient response to treatment. In this Challenge Award, Dr. Lang and his team will carry out the necessary work to automate and validate VERSA so that it can be used across the country in both large hospitals and small. They will conduct a multi-site clinical trial that uses VERSA to examine individual patient’s initial and ongoing reactions to treatment with two drugs (Xtandi and the investigational compound ARN-509) that target a key driver of prostate cancer progression—the androgen receptor. Drugs that target the androgen receptor have clearly been shown to benefit many men with advanced, metastatic prostate cancer; however, ultimately, even men who respond well to these drugs eventually develop resistance to them. This research, by Drs. Lang, Beebe, Bruce and Stein, will help determine how and why men develop resistance to AR-targeting drugs and what might be done to prevent or stall the development of drug resistance.

What this means for patients: Understanding cancer at the individual level is the goal of personalized and precision medicine. Dr. Lang and his team have developed an advanced technology that will allow doctors to peer into the individual cancer cell at the molecular level to determine what is driving a cancer at each stage of progression. This is a very important step in the ability to fully personalize cancer treatments to each patient’s cancer, even to each tumor in patients with metastatic disease. Dr. Lang and his team are developing and validating a new blood testing technology that can monitor disease progression, patient response to treatment, and the unique genetic fingerprint of individual cancer cells so treatment by location or type of mutation might be delivered. Their technology platform, VERSA, will also be used to understand why some patients are initially resistant to certain anti-cancer medications or become so as treatment progresses. This understanding can then be used to develop ways to prevent drug resistance and extend patient survival.

Principal Investigator:

Josh Lang, MD (University of Wisconsin)

Co-investigators:

David Beebe, PhD (University of Wisconsin), Justine Bruce, MD, (University of Wisconsin), Mark Stein, MD (Robert Wood Johnson Medical School).