Imanouel Tsimchi

Introduction. Prostate Cancer is the most prevalent non-dermatological cancer and the third leading cause of death in men with 60,000 new diagnoses every year 30,000 deaths in the United states¹. It commonly presents in men age at the age 66 of with urinary hesitancy, nocturia, or may even be asymptomatic.¹ Although survivability of the cancer is high, there are a number of cases progressing to castration resistant prostate cancer (CRPC) which survives common treatment.^2-3 Studies have found multiple mechanisms such as constitutively active androgen receptors and upregulation of accessory proliferation pathways in the face of one type of inhibition treatment.^4-5 These findings suggest that co-administering multiple methods of treatment may prevent resistance.^5-6  Methods: The first study used reverse-transcriptase–polymerase-chain-reaction assay to evaluate Androgen Receptor Variant 7 (AR-V7) in CRPC patients and assess prostate specific antigen (PSA) levels after administering androgen receptor blockers Abiraterone and Enzalutamide.⁴ The second study had 12 human patients with CRPC receive PI3K/AKT inhibition in the form of Gefitinib and Everolimus and then measured PSA levels afterwards.⁵ In these studies PSA levels are used as a marker to determine prostate cancer progression^4-5.  A third study used CRPC rats and treated them with just Androgen Receptor blockers, only PI3K/AKT inhibitors, and a combination of the two to determine the efficacy of combined treatment.⁶ Tumor volume of the mice was used to determine treatment effectiveness.⁶ Results: The first study found that administering androgen receptor blockers to patients with AR-V7 had a continuous increase in PSA levels while patients who were AR-V7 negative had a marked increase in PSA levels.⁴ The second study found that inhibiting only the PI3K/AKT pathway lead to a marked increase in PSA levels as well.⁵. In the study with dual inhibition, it was found that in mice treated with both PI3K/AKT inhibitors and Androgen receptor blockers, tumor volume was significantly reduced.⁶       Conclusions: Studies show that ARV7 is a constitutively active androgen receptor and studies show that regardless of drug inhibition the tumor will proliferate.⁴ This suggests that steps to forego medication and proceed straight to surgical intervention are appropriate for patients with this-receptors.⁴ Additionally, studies suggest an upregulation of Androgen receptors in the case of sole PI3K/AKT inhibition.⁵ The same studies also suggests that the pathways are linked  and that there is plausible evidence for dual treatment of both pathways to be efficacious and in human trials.^5-6

1. Litwin MS, Tan H. The Diagnosis and Treatment of Prostate Cancer: A Review. 2017;317(24):2532–2542. doi:10.1001/jama.2017.7248
2. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2018. CA: A Cancer Journal for Clinicians. 2018;68(1):7-30. doi:10.3322/caac.21442
3. Antonarakis ES. Current Understanding of Resistance to Abiraterone and Enzalutamide in Advanced Prostate Cancer. Clinical Advances in Hematology & Oncology. 2016;14(5):316-319.
4. Antonarakis ES, Lu C, Wang H, et al. AR-V7 and Resistance to Enzalutamide and Abiraterone in Prostate Cancer. New England Journal of Medicine. 2014;371(11):1028-1038. doi:10.1056/nejmoa1315815
5. Rathkopf DE, Larson SM, Anand A, et al. Everolimus combined with gefitinib in patients with metastatic castration-resistant prostate cancer: Phase 1/2 results and signaling pathway implications. Cancer. 2015;121(21):3853-3861. doi:10.1002/cncr.29578
6. Marques RB, Aghai A, Ridder CMD, et al. High Efficacy of Combination Therapy Using PI3K/AKT Inhibitors with Androgen Deprivation in Prostate Cancer Preclinical Models. European Urology. 2015;67(6):1177-1185. doi:10.1016/j.eururo.2014.08.053