Q&A: Dr. Patrick Pilié- 2018 KCA Young Investigator Award Recipient

In honor of our 30th anniversary, we’re catching up with former grant recipients to hear how their work has impacted kidney cancer care and research.

Dr. Patrick Pilié is an Assistant Professor in the Department of Genitourinary Medical Oncology at MD Anderson Cancer Center in Houston, Texas. Dr. Pilié received the 2018 Kidney Cancer Association Young Investigator Award. We spoke to him about his research project –  Identifying and targeting DNA damage response deficiency in clear cell renal cell carcinoma – and what he’s been working on recently.

What was the inspiration for the research you were granted funds for? How did the project come together?

Dr. Pilié – Starting with my own family’s experience with cancer, I have had a longstanding interest in hereditary forms of cancer. I have a passion for research that focuses on a deeper understanding of the molecular underpinnings of cancer initiation and progression so that we can better tailor treatments for our patients. Genomic instability is a hallmark of all cancers, including kidney cancer, and arises due to extreme stress on the cancer cell combined with defects in the cell’s ability to repair DNA. Kidney cancer is notoriously resistant to DNA damaging chemotherapies, and it is not well understood how VHL loss in kidney cancer influences genomic instability. My project that was funded through the KCA’s YIA program was focused on identifying the engines of instability in kidney cancer, understanding how VHL loss affects DNA damage response (DDR) signaling, and testing targeted inhibitors specifically chosen because of those identified derangements in DDR.

What was the outcome of the research project? Have there been further outcomes or developments following the award period?

Dr. Pilié – Through genomic and proteomic profiling of kidney tumors from patients with VHL syndrome, we identified that biallelic loss of VHL is sufficient to induce genomic instability and leads to defective DDR protein activation, including activation of ATM, a key regulator of genomic instability and DDR across cancer types. We then have validated in preclinical models that indeed VHL loss leads to defective ATM activation and increased error-prone DNA repair. These defects are targetable with a new class of inhibitors called ATR and CHEK1 inhibitors, amongst others. We then tested the anti-cancer impact of ATR inhibitors in kidney cancer models, finding that VHL loss can engender sensitivity to these inhibitors. Furthermore, these inhibitors may also induce an innate immune response and improve outcomes when combined with immune checkpoint therapy. We are actively investigating this combination for patients with kidney cancer and other solid malignancies in the lab and in clinical trials.

How would you say your research project contributed to the field?

Dr. Pilié – Despite significant advances in the treatment of kidney cancer with immune therapy and tyrosine kinase inhibitors, metastatic kidney cancer remains lethal. There is a significant need for novel, biologically informed treatment strategies to improve the duration and depth of response for patients with VHL-aberrant kidney cancer and VHL syndrome. Targeting genomic instability with DDR inhibitors in combination with immune checkpoint blockade and/or targeted inhibitors in a biomarker-selected fashion holds great promise for patients with kidney cancer.

What did you find most exciting or significant about your research? How would you explain this to a person with kidney cancer?

Dr. Pilié – We now have a better understanding of the genetics behind kidney cancer, and how VHL loss (the founding molecular event in essentially all clear cell renal cell carcinoma) contributes to cancer cell initiation and progression through defective DDR signaling. This research contributes to the growing evidence that we can target genomic instability in kidney cancer with novel targeted inhibitors, and hopefully expand the number of patients who benefit from immune and targeted therapies.

Did this research project impact your approach to patient care?

Dr. Pilié – Yes, this project affirmed my passion to continue to serve patients with hereditary cancer syndromes. Patient-centered research in individuals with hereditary cancer syndromes can also greatly inform molecular characterization and treatment opportunities in patients with sporadic versions of cancer.

What is your research focus now?

Dr. Pilié – My research continues to focus on targeting replication stress and DDR in biologically rational clinical trials for patients with genitourinary malignancies including kidney and prostate cancer. I also continue to lead clinical endeavors and research in genitourinary genetics.

Is there anything else you’d like patients and families to know about the impacts of your work?

Dr. Pilié – I would like to express my most sincere gratitude to patients and their families for trusting us with your care and for participating in clinical research through trials and tissue donation, as this research would not be possible without them. Their contributions will improve the lives of all patients with cancer, and we are all deeply indebted for that.