Draft:Adaptive therapy

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Adaptive therapy is an approach to cancer therapy based on concepts from integrated pest management for maintaining control over pests that evolve pesticide resistance..[1] The approach depends on the observation that resistance to drugs, be they pesticides or cancer therapies, comes at some cost to the organism. This implies that cancer cells that are sensitive to the drug can out-compete cancer cells that are resistant to the drug, in the absence of the drug. The strategy of adaptive therapy is to maintain drug-sensitive cells in the tumor so that they can out-compete the drug-resistant cells and keep them under control. This is a fundamental shift from trying to cure cancer, to trying to control cancer, indefinitely. The goal is to allow people to live with their cancers but not die from their cancers.

In contrast, the standard of care for most cancers is based on using the maximum tolerated dose of the drug, which typically kills all the drug-sensitive cancer cells, leaving behind the drug-resistant cancer cells that suddenly have no competitors, a phenomenon known in ecology as competitive release. Typically, it is these drug-resistant cancer cells that kill patients with cancer, if the patient does not succumb from the toxicity of the drugs themselves.

There are two main types of adaptive therapy, dose adjustment and drug holidays. The dose adjustment strategy is to treat frequently, raising the dose when the tumor grows, but lowering the dose when the tumor shrinks. The drug holiday strategy uses a fixed dose, but stops dosing when the tumor shrinks below some threshold (e.g., half of its original size). It then resumes dosing when the tumor grows above some threshold (e.g., the original size of the tumor).

Adaptive therapy experiments in mice[edit]

Adaptive therapy based on dose adjustment was effective at maintaining long-term control over a human ovarian[2] cancer engrafted into immunocompromised mice, as well as a triple negative breast cancer cell line, and an estrogen receptor positive breast cancer engrafted into immunocompromised mice[3]. However, the drug holiday strategy was not effective at controlling either of the breast cancer cell lines (it was not tried on the ovarian cancer)[3]

One surprise of these experiments was the observation that control of the cancers required less and less drug over time[2][3]. Later experiments showed that tumors treated with the adaptive therapy protocol had better perfusion of blood vessels than tumors treated with the maximum tolerated dose[3]. This implies that adaptive therapy resulted in more efficient delivery of the drug to the tumors compared to the maximum tolerated dose protocol.

Clinical trial results[edit]

Based on the results of the mouse experiments, the first clinical trial of adaptive therapy was opened to treat castration resistant, metastatic prostate cancer at the Moffitt Cancer Center in Tampa Florida[4]. Initially, tt was a small pilot trial of 11 men, using the drug holiday version of adaptive therapy. At the time, the standard of care for men with this condition was continuous treatment with abiraterone, which inhibits the synthesis of testosterone. Typically, prostate cancer cells require testosterone in order to proliferate. In a previous, large randomly controlled trial, half of the prostate cancers treated continuously with abiraterone started to grow again within 16.5 months[5]. This is called the median time to progression. Results of the adaptive therapy pilot trial were published when only 1 of the 11 men's cancers had started grow out of control[4]. They achieved control of the tumors for a median of at least 27 months. The median time to progression has not been published yet. Notably, at the time of publication, the men in the adaptive therapy protocol had only received 47% of the total amount of abiraterone compared to a cohort of men that were being treated with the standard of care for castration resistant, metastatic prostate cancer.

On going and planned clinical trials[edit]

Currently there are 3 open clinical trials of adaptive therapy are actively accruing at the Moffitt Cancer Center, these include one for first line prostate cancer treatment led by Dr. Jingsong Zhang,[6] thyroid cancer led by Dr. Christine Chung,[7] and melanoma led by Dr. Zeynep Ergolu.[8] A small pilot trial in metastatic, triple negative breast cancer and estrogen receptor positive metastatic breast cancer is scheduled to open at the Mayo Clinic's Arizona campus in 2019, led by Dr. Donald Northfelt.

Role of mathematical modeling[edit]

Mathematical models have played a central role in the development of adaptive therapy. Evolutionary Game Theory in particular was a driver in the decision when a treatment should stop or begin, the 50% drop in PSA that was used in the prostate trial above[4] was based on model predictions discussed in the same paper. Other game theory work by Stankova et al.[9] consider adaptive therapy through the lens of leader-follower (or "Stackelberg") games. Subsequent work by Gallaher et al.[10] consider the importance of space in constraining resistant cells.

References[edit]

  1. ^ Khamsi, Roxanne (25 March 2019). "A Clever New Strategy for Treating Cancer, Thanks to Darwin". Wired. Retrieved 1 April 2019.
  2. ^ a b Gatenby, R. A.; Silva, A. S.; Gillies, R. J.; Frieden, B. R. (2009). "Adaptive Therapy". Cancer Research. 69 (11): 4894–4903. doi:10.1158/0008-5472.CAN-08-3658. ISSN 0008-5472. PMC 3728826. PMID 19487300.
  3. ^ a b c d Enriquez-Navas, P. M.; Wojtkowiak, J. W.; Gatenby, R. A. (2015). "Application of Evolutionary Principles to Cancer Therapy". Cancer Research. 75 (22): 4675–4680. doi:10.1158/0008-5472.CAN-15-1337. ISSN 0008-5472. PMID 26527288.
  4. ^ a b c Zhang, Jingsong; Cunningham, Jessica J.; Brown, Joel S.; Gatenby, Robert A. (2017). "Integrating evolutionary dynamics into treatment of metastatic castrate-resistant prostate cancer". Nature Communications. 8 (1): 1816. Bibcode:2017NatCo...8.1816Z. doi:10.1038/s41467-017-01968-5. ISSN 2041-1723. PMID 29180633.
  5. ^ Ryan, Charles J.; Smith, Matthew R.; de Bono, Johann S.; Molina, Arturo; Logothetis, Christopher J.; de Souza, Paul; Fizazi, Karim; Mainwaring, Paul; Piulats, Josep M.; Ng, Siobhan; Carles, Joan; Mulders, Peter F.A.; Basch, Ethan; Small, Eric J.; Saad, Fred; Schrijvers, Dirk; Van Poppel, Hendrik; Mukherjee, Som D.; Suttmann, Henrik; Gerritsen, Winald R.; Flaig, Thomas W.; George, Daniel J.; Yu, Evan Y.; Efstathiou, Eleni; Pantuck, Allan; Winquist, Eric; Higano, Celestia S.; Taplin, Mary-Ellen; Park, Youn; Kheoh, Thian; Griffin, Thomas; Scher, Howard I.; Rathkopf, Dana E. (2013). "Abiraterone in Metastatic Prostate Cancer without Previous Chemotherapy". New England Journal of Medicine. 368 (2): 138–148. doi:10.1056/NEJMoa1209096. ISSN 0028-4793. PMC 3683570. PMID 23228172.
  6. ^ https://clinicaltrials.gov/ct2/show/NCT03511196
  7. ^ https://clinicaltrials.gov/ct2/show/NCT03630120
  8. ^ https://clinicaltrials.gov/ct2/show/NCT03543969
  9. ^ Stanková, Katerina; Brown, Joel S.; Dalton, William S.; Gatenby, Robert A. (2019). "Optimizing Cancer Treatment Using Game Theory". JAMA Oncology. 5 (1): 96. doi:10.1001/jamaoncol.2018.3395. ISSN 2374-2437. PMID 30098166.
  10. ^ Gallaher, Jill A.; Enriquez-Navas, Pedro M.; Luddy, Kimberly A.; Gatenby, Robert A.; Anderson, Alexander R. A. (2017). "Spatial heterogeneity and evolutionary dynamics modulate time to recurrence in continuous and adaptive cancer therapies". doi:10.1101/128959. Cite journal requires |journal= (help)