Sequential Hormone Therapy for CRPC Treatment Resistance
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Solution Overview
Problem
Prostate cancer becomes lethal once it escapes the prostate gland, and current androgen ablation therapies eventually fail due to the upregulation of androgen receptor (AR) signaling, leading to castration-resistant prostate cancer (CRPC), with existing treatments showing modest survival benefits and unknown long-term effects.
Innovation Solution
A sequential hormone therapy regimen involving supraphysiological doses of androgens followed by antiandrogens and androgen synthesis inhibitors, alternating treatment cycles based on prostate-specific antigen (PSA) levels, and optionally combined with immune checkpoint blockade.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If androgen ablation therapy is used to treat prostate cancer, then initial treatment effectiveness is improved, but resistance develops over time due to AR upregulation
Solution Approach 1:
The patent implements periodic action through alternating cycles of androgen administration and androgen deprivation therapy. Patients receive supraphysiological doses of androgen for a specified period, followed by androgen deprivation therapy, creating a rhythmic treatment pattern that exploits cancer cell adaptation cycles. This periodic approach prevents continuous resistance development while maintaining initial treatment effectiveness.
Solution Approach 2:
The patent applies parameter changes by dynamically adjusting androgen levels from supraphysiological doses to castrate levels, and subsequently to low physiological levels during the luteal phase. This parameter modulation strategy targets cancer cells at different sensitivity states, preventing resistance while maintaining treatment effectiveness throughout the treatment cycle.
2Productivity
If chronic androgen deprivation is applied, then initial tumor growth is suppressed, but AR upregulation occurs leading to treatment resistance
Solution Approach 1:
The patent applies preliminary action by administering supraphysiological doses of androgen before initiating androgen deprivation therapy. This preliminary androgen exposure prevents the cancer cells from immediately adapting to androgen deprivation by upregulating AR, as the cells are already exposed to high androgen levels that suppress AR expression mechanisms.
Solution Approach 2:
The patent implements preliminary anti-action by using high-dose androgen therapy to counteract the adaptive response to androgen deprivation. The supraphysiological androgen levels prevent the harmful AR upregulation that would otherwise occur during chronic androgen deprivation, thereby maintaining tumor growth suppression without inducing resistance.
3Reliability
If high doses of androgen are administered, then CRPC cell growth is inhibited, but long-term continuous administration may reduce effectiveness
Solution Approach 1:
The patent employs periodic action by administering high-dose androgen therapy in discrete cycles rather than continuously. Each cycle consists of androgen administration followed by androgen deprivation, creating periodic high-androgen exposure that maintains CRPC growth inhibition while preventing the diminishing returns associated with continuous therapy.
Solution Approach 2:
The patent applies dynamics by making the androgen dosage flexible and time-dependent. The treatment protocol adjusts androgen levels dynamically based on the treatment phase (supraphysiological during follicular phase, castrate during luteal phase), optimizing CRPC growth inhibition at each stage while maintaining long-term therapy effectiveness through adaptability.
Data Source
AI summary
Disclosed are methods for treating men with castrate resistant prostate cancer with a sufficient dose of testosterone to achieve supraphysiologic serum levels of testosterone in sequence with androgen ablative treatment or androgen synthesis inhibitors for one or more cycles until evidence of radiographic progression, at which point the subject will receive immune checkpoint blockade therapy.