Research Plan:

Radiation therapy is one of the primary treatment modalities for patients with prostate cancer. Decisions about the intensity of therapy, with regards to radiation dose, targets, and the addition of hormone treatment to radiation, are often based upon assessment of the risk of disease recurrence. While the risk of disease recurrence can be approximated by conventional parameters such as tumor histology (Gleason score), extent of tumor on physical exam (T stage), and blood tests (PSA levels), there is a compelling need for identification of additional biomarkers to improve the prediction of recurrence risk, with the goal of tailoring radiotherapy for prostate cancer for each patient on an individual basis.

Over the past few years, fusion genes, or hybrid genes formed from the union of two previously separate genes, have been identified in greater than 45% of prostate cancers. These fusion genes result in the abnormal regulation of the ETS family of transcription factors, which are proteins that control the transfer of genetic information from DNA to RNA. Increased expression of these transcription factors has been demonstrated to correlate with/convey aggressive tumor behavior in cell systems and in mouse tumor models within the laboratory. However, to date, few details are known about the mechanisms by which these gene fusion products mediate their effects. Additionally, it is unknown how these gene fusion products affect the response to radiation therapy.

Our research group has recently discovered that ERG, a member of the ETS family of transcription factors, physically interacts with a critical component of repair pathways for DNA double-stranded breaks, the DNA-dependent protein kinase (DNAPK). Because radiation relies upon DNA damage in tumors for its effectiveness, we hypothesize that increased expression of ERG confers resistance to radiation therapy in prostate cancer. In this proposal, we aim to (1) determine the effect of ERG on radiation sensitivity in cellular and mouse models of prostate cancer, and examine how this effect is modulated by hormone treatment and inhibition of DNAPK; (2) evaluate the mechanism of the interaction between ERG and DNAPK; and (3) evaluate whether ETS gene fusion status is an independent predictive biomarker of resistance to radiation therapy, in prostate cancer tumor samples from men treated with radiation for prostate cancer.

This novel research may have a significant impact on the risk assessment and individualization of radiation therapy for prostate cancer patients. If ERG overexpression is confirmed to result in radioresistance, ETS gene fusion status may be used to determine which patients should have treatment intensification with radiation dose escalation, and which patients should be spared the toxicity associated with treatment intensification. Additionally, this research would provide strong rationale for targeted radiosensitization of ETS-positive patients through inhibition of DNAPK, opening a realm of possible treatment options for these patients.

Training Plan:

This proposal also includes a training plan, with a goal to assist Dr. Feng in completing his transition to independence, as an investigator who seeks to improve the care received by prostate cancer patients through advances in translational research. Specifically, Dr. Feng's career goals are to individualize radiation therapy for prostate cancer by developing better prognostic indicators and predictors of recurrence risk, based on the molecular biomarkers in each patient's tumor. To reach this goal, he has assembled a strong team of mentors, comprised of Dr. Arul Chinnaiyan, Dr. Theodore Lawrence, and Dr. Thomas Carey, all of whom are national leaders in biomarker research. With the guidance of his mentors, Dr. Feng has devised a training program which integrates advanced contextual training within the laboratory setting with components directed toward basic research (seminar series, bioinformatics courses, journal clubs), clinical translation (prostate-focused clinical service, multidisciplinary conferences for genitourinary malignancies, clinical trials workshop), and national outlook (regional and national conferences). Dr. Feng's training and research programs provide a combination of benchtop experience, didactic and interactive learning, and clinical training which will provide him a strong foundation toward his career goals of evaluating biomarkers of radiation response and implementing them into clinical practice.