Multidrug Cancer Therapy in Metastatic Castrate-Resistant Prostate Cancer: An Evolution-Based Strategy

West, Jeffrey; Dinh, Mina N.; Brown, Joel S.; Zhang, Jingsong; Anderson, Alexander R.A.; Gatenby, Robert A.

doi:10.1158/1078-0432.ccr-19-0006

Cited by 94 publications

(115 citation statements)

References 43 publications

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“…Given the key role which prostate cancer has played in the development of adaptive therapy we parametrise our model according to this disease. As such, we adopt the proliferation rate for sensitive cells given in [11] (r S = 0.027d −1 ) as our time scale and the drug kill parameterd D = 1.5 from [30]. For the other parameters we perform parameter sweeps within their biologically realistic ranges.…”

Section: Parameterising the Modelmentioning

confidence: 99%

Turnover modulates the need for a cost of resistance in adaptive therapy

Strobl

West

Viossat

et al. 2020

Preprint

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Control and conquer" -this is the philosophy behind adaptive therapy, which seeks to exploit intra-tumoural competition to avoid, or at least, delay the emergence of therapy resistance in cancer. Motivated by promising results from theoretical, experimental and, most recently, a clinical study in prostate cancer, there is an increasing interest in extending this approach to other cancers. As such, it is urgent to understand the characteristics of a cancer which determine whether it will respond well to adaptive therapy, or not. A plausible candidate for such a selection criterion is the fitness cost of resistance. In this 1 paper, we study a simple competition model between sensitive & resistant cell populations to investigate whether the presence of a cost is a necessary condition for adaptive therapy to extend the time to progression beyond that of a standard-of-care continuous therapy. We find that for tumours close to their environmental carrying capacity such a cost of resistance is not required. However, for tumours growing far from carrying capacity, a cost may be required to see meaningful gains. Notably, we show that in such cases it is important to consider the cell turnover in the tumour and we discuss its role in modulating the impact of a cost of resistance. Overall, our work helps to clarify under which circumstances adaptive therapy may be beneficial, and suggests that turnover may play an unexpectedly important role in the decision making process.

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Section: Parameterising the Modelmentioning

confidence: 99%

Turnover modulates the need for a cost of resistance in adaptive therapy

Strobl

West

Viossat

et al. 2020

Preprint

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“…This eco-evolutionary inspired paradigm for cancer treatment known as 37 "adaptive therapy" capitalizes on subclonal competitive interactions. Resistance may confer some fitness costs due to increased 38 rates of DNA repair or other costly activities required to pump toxic drugs across cell membranes. Cancer cell resistance 39 mechanisms, whether mitigation, detoxification, or re-routing metabolic pathways, divert finite resources that would otherwise 40 be available for cell proliferation or other avenues for cell survival 14,22,25 .…”

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“…D) An alternative multi-drug adaptive strategy is to administer both drugs simultaneously during each on-off cycle, leading to a doubly-resistant resistant clone (yellow). therapies remains difficult 38 . Second, it's not yet clear how to extend these evolutionarily enlightened therapeutic concepts to 55 multiple treatments.…”

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“…This model suggests that even with adaptive therapy, disease progression 96 can be greatly delayed but remains inevitable (see figure 3A,C). In figure 3, we present data of representative patients from 97 NCT02415621 who have undergone at least five adaptive doses of treatment at the time data was acquired 28,38 . Next, we 98 parameterize a previously published Lotka-Volterra model of treatment dynamics (see refs.…”

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“…Next, we 98 parameterize a previously published Lotka-Volterra model of treatment dynamics (see refs. 28,38,45 ), by fitting the model to 99 prostate-serum-antigen blood biomarker (PSA) data from all patients (figure 3, dashed red lines).…”

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Towards multi-drug adaptive therapy

West

Brown

et al. 2018

Preprint

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A new ecologically inspired paradigm in cancer treatment known as "adaptive therapy" capitalizes on competitive interactions between drug-sensitive and drug-resistant subclones. The goal of adaptive therapy is to maintain a controllable stable tumor burden by allowing a significant population of treatment sensitive cells to survive. These, in turn, suppress proliferation of the less fit resistant populations. However, there remain several open challenges in designing adaptive therapies, particularly in extending these therapeutic concepts to multiple treatments. We present a cancer treatment case study (metastatic castrate resistant prostate cancer) as a point of departure to illustrate three novel concepts to aid the design of multi-drug adaptive therapies. First, frequency-dependent "cycles" of tumor evolution can trap tumor evolution in a periodic, controllable loop. Second, the availability and selection of treatments may limit the evolutionary "absorbing region" reachable by the tumor. Third, the velocity of evolution significantly influences the optimal timing of drug sequences.Dobzhansky's now-famous quote that "nothing in biology makes sense except in the light of evolution" succinctly explains 1 a worldview that has been widely adopted by the cancer biology community 1 . Taken one step further, others have claimed 2 that "nothing in evolution makes sense except in the light of ecology" which provided the basis for designing adaptive cancer 3 therapies centered on principles from evolution and ecology 2-4 . 4 Cancer is an evolutionary and ecological process 5, 6 driven by random mutations 7, 8 responsible for the genetic diversity 5 and heterogeneity that typically arises via waves of clonal and subclonal expansions 9, 10 . Clones and subclones compete and 6 Darwinian selection favors highly proliferative cell phenotypes, which in turn drive rapid tumor growth 5, 6 . 7Recent emphasis on personalized medicine has largely focused on the development of therapies that target specific mutations. 8These targeted therapies do extend patient lives but cancer cells tend to evolve resistance within months or years 11, 12 . Prior 9 to therapy, pre-existing resistant cell types are suppressed and kept in check by competitively superior, therapy-sensitive cell 10 types. There is some evidence of "cost" to incurring resistant mutations. In one study, cells sensitive (MCF7) and resistant 11 (MCF7Dox) to doxorubicin cocultured in vitro showed that sensitive MCF7 cells rapidly outcompeted the resistant MCF7Dox 12 line after only a few generations, illustrating the "cost" of resistance cell lines co-cultured with drug-sensitive cell lines. 13 . 13With a targeted therapy suppressing sensitive cells, these resistant cell types may experience release from competition 14 . If 14 total eradication of all cancer cells is not accomplished, the tumor will relapse derived from resistant cells that survived initial 15 therapy 15,16 . Upon relapse, a second drug may be administered. Yet continuous use of this subsequent targeted...

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An evolutionary framework for treating pediatric sarcomas

Reed

Metts

Pressley

et al. 2020

Cancer

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Patients and families affected by sarcomas often ask, "What is cancer?" Answers frequently portray cancer as mutant cells gone rogue with rapid, uncontrolled, and even zombie-like growth. This analogy may be helpful for encouraging compliance during chemotherapy, when cure requires enduring significant toxicity. However, this "zombie" paradigm understates cancer's most lethal and sophisticated property-its ability to evolve. [1][2][3][4] In contrast, viewing cancer as an invasive and evolving species may provide a more accurate and accessible analogy. This model "normalizes" cancer cells by emphasizing their obedience to the same laws of ecology and evolution that govern all living systems. Within this framework, the Darwinian dynamics of evolution can be leveraged to improve understanding of tumor growth and resistance.Normal mammalian cells do not evolve because their fates are determined by collective tissue controls, making their fitness (for a Glossary of Terms, see Table 1) identical to that of the host organism. Fundamentally, cancer is a shift in the order of natural selection from the host level to that of an individual cancer cell. This new, "self-defined" fitness function of the cancer cell can be considered a speciation event. 3 In becoming a singular unit of natural selection, a cancer cell must respond to external influences from the host environment. To understand malignancy as a complex, adapting system of cancer cells, we introduce key terms and emerging theories from evolutionary biology that may translate into novel clinical trials. Although evolutionary principles are applicable to many cancer types across adult and pediatric oncology, here, we apply these concepts to pediatric sarcoma, using an evolution-inspired clinical trial in metastatic fusion-positive rhabdomyosarcoma (FPRMS) as an illustration. PEDIATRIC SARCOMASSarcomas, such as osteosarcoma, Ewing sarcoma, and rhabdomyosarcoma, collectively make up 10% of malignancies in children and young adults. Even when disease is clinically localized at presentation, surgery and/or radiation alone is usually insufficient for cure, as a majority of patients will relapse, frequently through development of distant metastases. Because there are no current ways to identify patients who can be cured by local control alone, chemotherapy is recommended for all patients. Cure rates increase up to 65% to 80% for localized disease with the addition of combination chemotherapy. [5][6][7][8][9] Although there is a growing understanding of the genetic features distinguishing sarcoma cells from somatic cells, the most successful treatments target pathways common to tumor and normal cells alike, so-called "never mutated pathways," such as DNA synthesis and replication, topoisomerase-mediated DNA repair, and microtubule function. 2,10-15 Unfortunately, outcomes for metastatic pediatric sarcomas have changed little over the past 2 decades, and the prognosis for metastatic pediatric sarcomas remains dismal. [16][17][18] The application of evolutionary concepts to ...

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Multidrug Cancer Therapy in Metastatic Castrate-Resistant Prostate Cancer: An Evolution-Based Strategy

Cited by 94 publications

References 43 publications

Turnover modulates the need for a cost of resistance in adaptive therapy

Turnover modulates the need for a cost of resistance in adaptive therapy

Towards multi-drug adaptive therapy

An evolutionary framework for treating pediatric sarcomas

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