I was asked to post this by George71--very interesting stuff especially the material about intermittent use of two treatments.
Cancer Therapy, Adapting to Change the Game
Robert Gatenby, MD
The Moffitt Cancer Center
•Cancer is often described as a disease of the genes. While cancer cells clearly accumulate genetic alterations that collectively confer continued proliferation, resistance to normal cell death signals, and the ability to metastasize, cancer cells are imbedded in a temporally and spatially variable tissue ecosystem which ultimately selects the phenotypic properties (and their genotypic counterparts) that are most fit.
•Thus, cancer is more than a disease of the genes. It is a complex, dynamic system with multiple non-linear interactions. Understanding these non-linear interactions will improve our ability to predict the outcomes of treatments that perturb a complex dynamic system and develop improved treatments.
•These complexities can be addressed by recruiting mathematicians and evolutionary biologists to the study of cancer, and linking them with clinicians, to develop theoretical understandings of the dynamics of cancer evolution in cancer treatment. This integrated
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research approach is being taken through the Integrated Mathematical Oncology (IMO) Department and the Cancer Biology and Evolution (CBE) program at the Moffitt Cancer Center.
•Dr. Robert Gatenby discussed studies to integrate evolutionary dynamics into prostate cancer therapy.
•Currently, oncology research focuses on developing new drugs which are typically used at “maximum tolerated doses” (MTDs). MTD is the highest concentration of a drug that patients can tolerate without experiencing unacceptable side effects.
•The goal of using cancer drugs at maximum tolerated dose levels, is to kill as many cancer cells as possible. However, this treatment approach typically results in selection for treatment-resistant cancer cells, which eventually proliferate, repopulate the tumor, and cause disease progression.
•Because of the diversity of cancer cells (mutations and gene expression patterns can be different in each cell) and the diversity of the tumor microenvironment (for instance, some areas of the tumor are more accessible to therapy than others), drug-resistant cells are often present prior to therapy, and are selected for by the treatment.
•The field of evolutionary biology has found that genes which are not necessary are often a burden to an organism and will be lost over time. For instance, Charles Darwin discovered a species of fish that live in dark underwater caves and had evolved to loose eyes.
•Similarly, resistance to therapy may be a burden to a cancer cell when it is not necessary because it requires expenditure of resources for synthesis, maintenance, and operation of the molecular machinery of resistance. While the resource costs are exceeded by the corresponding benefit during treatment, they are wasted when therapy is not present. Thus, in the absence of treatment, treatment-resistant cells may be less fit and competitive compared with treatment-sensitive cells.
•These principles led to the hypothesis that treatment of cancer with lower or less frequent doses of cytotoxic drugs may be more effective in the long term, as populations of chemotherapy-sensitive cells would be maintained and would suppress the growth of chemotherapy-resistant cells when the treatment is removed. In this treatment approach, the goal is to maintain a steady-state tumor burden. Lower doses of drug would also be less toxic to patients.
•An “adaptive therapy” treatment approach was tested in animal models, in which the chemotherapy dose was continuously modified to maintain a stable tumor volume. Mice with exponentially growing tumors were initially given chemotherapy frequently, with progressively lower doses. When the tumor ceased to grow exponentially, reaching a “plateau,” tumor control was maintained using low doses of chemotherapy. In this study, treatment could be discontinued for long periods of time (months) in 67% of the mice, and tumor control was maintained indefinitely in 87% of the mice.
•Androgen receptor (AR)-targeted therapy, which acts to block the production or action of testosterone, is a primary treatment for advanced prostate cancer, and is typically given continuously until the tumor develops resistance and disease progression occurs.
Unfortunately, treatment resistance to AR-targeted therapy is common, and evolves through various mechanisms, including via tumor cells gaining the ability to produce their own testosterone.
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•An adaptive therapy trial was initiated to test intermittent administration of abiraterone in patients with metastatic castration-resistant prostate cancer (mCRPC). Abiraterone is a standard-of-care AR-targeted treatment for mCRPC that is typically given continually until disease progression.
•In the adaptive therapy trial, patients were given abiraterone until PSA levels dropped by
≥50%, at which time abiraterone treatment was discontinued. This was hypothesized to allow treatment sensitive cells to repopulate the tumor and suppress growth of treatmentresistant cells. Abiraterone was administered again when a patient’s PSA level returned to the pre-treatment level (one cycle), and then withdrawn when the PSA was reduced to 50% of the pretreatment value. Mathematical models predicted that tumor control with this approach could be maintained for 2 to 20 cycles of treatment.
•In preliminary analysis of the first 18 patients enrolled on this trial, cycle lengths (length of time between treatments) ranged from 4 months to 1.5 years (Figure). The earliest disease recurrence in a patient was observed after 2 cycles. The longest survivors are still under treatment after 12 cycles (~4 years). Thus far, four patients have experienced PSA and radiographic progression (at 12, 27, 30, and 32 months). However, the median time to progression for the treatment cohort has not yet been reached.
•These results were compared with a group of mCRPC patients contemporaneously treated with abiraterone in the continuous, standard-of-care manner (Figure). All 16 of the patients in the continuous abiraterone group have progressed, with a median time to radiographic progression of 15 months.
•Based on these results, an adaptive therapy approach for abiraterone in mCRPC appears promising, although a randomized trial comparing these treatment approaches is necessary to validate the superiority of one approach over the other. Notably, on average, patients treated on the adaptive therapy trial received less than half the cumulative dose of abiraterone as patients being treated continuously.
•Data from the patients being treated on this trial is now being used to generate mathematical models to improve the timing and duration of therapy. For instance, simulations using one patient’s data predicted that if abiraterone had been withdrawn when PSA reached 80% of the pre-treatment value (instead of 50%), cycle times would have been shorter but tumor control could have been maintained for almost twice the length of time.
•Mathematical simulations also predict that if an adaptive therapy approach is used with two drugs instead of one (abiraterone and docetaxel), time to disease progression could be increased four-fold.
•Based on these types of evolutionary principles and math models, Moffitt Cancer Center has opened four new adaptive therapy trials in several cancer types, including a trial testing firstline androgen deprivation therapy (ADT) for prostate cancer.
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Figure: Preliminary analysis of treatment lengths, cycles, and disease progression in mCRPC patients enrolled on a trial testing adaptive therapy with abiraterone (top) versus a group of mCRPC patients contemporaneously treated with abiraterone continuously (standard-of-care, SOC; bottom).
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Interesting paper summarising state of art (2022) for ADT
Syncromune Granted FDA Fast-Track Designation for SYNC-T SV-102 for the Treatment of Metastatic Castrate-Resistant Prostate Cancer (mCRPC)
