Mechanisms of resistance to intermittent androgen deprivation in patients with prostate cancer identified by a novel computational method.
For progressive prostate cancer, intermittent androgen deprivation (IAD) is one of the most common and effective treatments. Although this treatment is usually initially effective at regressing tumors, most patients eventually develop castration-resistant prostate cancer (CRPC), for which there is no effective treatment and is generally fatal. Although several biologic mechanisms leading to CRPC development and their relative frequencies have been identified, it is difficult to determine which mechanisms of resistance are developing in a given patient. Personalized therapy that identifies and targets specific mechanisms of resistance developing in individual patients is likely one of the most promising methods of future cancer therapy. Prostate-specific antigen (PSA) is a biomarker for monitoring tumor progression. We incorporated a cell death rate (CDR) function into a previous dynamical PSA model that was highly accurate at fitting clinical PSA data for 7 patients. The mechanism of action of IAD is largely induction of apoptosis, and each mechanism of resistance varies in its CDR dynamics. Thus, we analyze the CDR levels and their time-dependent oscillations to identify mechanisms of resistance to IAD developing in individual patients.
Authors' Affiliations: School of Mathematical and Statistical Sciences; Department of Chemistry and Biochemistry, Arizona State University, Tempe; and jmorken@asu.edu.
Jason D
JD
Morken
Authors' Affiliations: School of Mathematical and Statistical Sciences;
Aaron
A
Packer
Authors' Affiliations: School of Mathematical and Statistical Sciences;
Rebecca A
RA
Everett
Authors' Affiliations: School of Mathematical and Statistical Sciences; Department of Biology, Scottsdale Community College, Scottsdale, Arizona.
John D
JD
Nagy
Authors' Affiliations: School of Mathematical and Statistical Sciences;
Yang
Y
Kuang
D000465:Algorithms; D000728:Androgens / Q000378:metabolism*; D018931:Antineoplastic Agents, Hormonal / Q000627:therapeutic use*; D014408:Biomarkers, Tumor; D003198:Computer Simulation; D018450:Disease Progression; D019008:Drug Resistance, Neoplasm; D006801:Humans; D008297:Male; D008954:Models, Biological; D009919:Orchiectomy; D017430:Prostate-Specific Antigen; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology
D000728:Androgens; D018931:Antineoplastic Agents, Hormonal; D014408:Biomarkers, Tumor; D017430:Prostate-Specific Antigen