Prostate Cancer Resistance to First Line Treatments Involving the Androgen Receptor and AKT Pathway

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 progression4-5.  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

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