The COC Protocol™ in Melanoma

The COC Protocol is an individualized therapeutic approach which seeks to simultaneously target multiple cancer pathways. The COC Protocol may be considered in patients with melanoma, adjunctive to conventional cancer treatments.

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This graphic is a summary of some of the potential mechanisms of action reported for agents used in the COC Protocol as reported in the scientific literature. This is an evolving field of research, and this list is not exhaustive.

Targeting Cancer’s Metabolic Pathways

Metabolism is the conversion of food to energy to run cellular processes and construct cellular building blocks. It is widely accepted that the metabolism of cancer cells is usually fundamentally different to that of healthy non-cancerous cells. Altered metabolism is now considered a hallmark of cancer and a new discipline of “metabolic oncology” has emerged (Hanahan and Weinberg, 2000Hanahan and Weinberg 2011Bergers and Fendt, 2021).

Cancer cells need large amounts of energy to survive and grow. They commonly use an adaptive process called aerobic glycolysis (the ‘Warburg effect’) to generate the excessive energy they need (Kroemer and Pouyssegur, 2008Liberti and Locasale, 2016). The COC Protocol aims to target various molecular processes involved in and surrounding aerobic glycolysis and cancer metabolism. It aims to restrict cancer cell energy supply and use, while simultaneously preventing the cells from adapting and using other pathways to take up energy.

As a result of ongoing metabolic stress, the overall metabolic rate of the cancer cell could be lowered (Jang et al., 2013), and cancer cells may become weaker and less able to take in and use nutrients they need from their surroundings (e.g., glucose, lipids, and essential amino acids such as glutamine and arginine). This may potentially make it more difficult overall for cancer cells to survive, grow, spread, and adapt to changing conditions in the body (Martinez-Outschoorn et al., 2017Jagust et al, 2019Guerra et al., 2021).

Gradually, metabolically-weakened cancer cells (including more resilient and previously treatment-resistant cells) can potentially become more vulnerable to attack from other cell-killing cancer therapies such as radiotherapy, chemotherapy, and other therapies (Luo and Wicha, 2019Zhao et al, 2013Butler et al, 2013).

Using a Combination Approach

Review of peer-reviewed literature suggests that each individual element of the COC Protocol may target cancer cell metabolism in a distinct and potentially complementary way, and we have termed this action ‘mechanistic coherence’. Put simply, mechanistic coherence describes the possibility of attacking a cancer cell from different angles in what may be a synergistic or additive fashion. This type of combination approach in cancer is discussed by Mokhtari et al, 2017, and others.

Selected Melanoma-Related Research Publications

  • Metformin: Focus on Melanoma. Jaune E. and Rocchi S. 2018 PMID: 30186236
  • Is it time to test biguanide metformin in the treatment of melanoma? Cerezo M. et al. 2015 PMID: 24862830
  • Regulatory properties of statins and rho gtpases prenylation inhibitors to stimulate melanoma immunogenicity and promote anti-melanoma immune response.Sarrabayrouse G. et al. 2017 PMID: 27616679
  • Efficacy of PD-1 Blockade Is Potentiated by Metformin-Induced Reduction of Tumor Hypoxia. Scharping N.E. et al. 2017 PMID: 27941003
  • Cytotoxic and proapoptotic effect of doxycycline – An in vitro study on the human skin melanoma cells. Rok J. et al. 2020 PMID: 32044399
  • XIAP downregulation accompanies mebendazole growth inhibition in melanoma xenografts. Doudican N.A. et al. 2013 PMID: 23059386

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Further Research Publications

Mechanism 1Selection of Published Papers
Reduce availability of nutrients to cancer cell Rosilio C. et al. 2014 PMID: 24462823, Babcook M.A. et al. 2016. PMID: 27441003
Stimulate and facilitate immune response to cancer cell

Al Dujaily E. et al. 2020. PMID: 32190817, Yongjun Y. et al. 2013. PMID: 23707077,

Blom K. et al. 2017 PMID: 28472897, Bahrambeigi S. et al. 2019 PMID: 31884044,

Eikawa S. et al. 2015. PMID: 25624476, Kurelac I. et al. 2019 PMID: 31091466,

Lucero-Diaz P.A. et al. 2016 (Abstract), Tang H. et al. 2013 PMID: 23282955

Place cancer cells under ‘metabolic stress’

Pernicova I. et al. 2014. PMID: 24393785, Clendening J.W. et al. 2012. PMID: 22310279,

Guerra B. et al. 2021 PMID: 33718197, Huang B. et al. 2020. PMID: 32694690,

McGregor G.H. et al. 2020 PMID: 31562248, Petővári G. et al. 2018 PMID: 30574020

Modulate mitochondrial function in cancer cells

Ozsvari B. et al. 2017 PMID: 29080556, Cazzaniga M. et al. 2015 PMID: 26605341,

Missiroli S. et al. 2020 PMID: 32818805, Dijk S.N. et al. 2020 PMID: 32152409

Disrupt cancer cell growth and migration

Kamarudin M.N.A. 2019. PMID: 31831021, Jiang W. et al. 2021. PMID: 34303383,

Mukhopadhyay T. 2002 PMID: 12231542, Pinto L.C. et al. 2015 PMID: 26315676,

Yang B. et al. 2015 PMID: 26111245

Induce programmed cancer cell death (apoptosis)

Song H. et al. 2014 PMID: 25502932, Doudican N. et al. 2008 PMID: 18667591,

Sasaki J. et al. 2002 PMID: 12479701, Bayat N. et al. 2016 PMID: 27836464,

Cafforio P. et al. 2005 PMID: 15705602, Fromigué O. et al. 2006 PMID: 16470222,

Kalinsky K. et al. 2017 PMID: 27305912, Jiang W. et al. 2021. PMID: 34303383

Block cancer cell DNA damage repair

Efimova E.V. et al. 2018 PMID: 29030460, Lamb R. et al. 2015 PMID: 26087309,

Peiris-Pagès M. et al. 2015 PMID: 26425660 

Slow growth of tumor-feeding blood vessels (anti-angiogenic activity)

Bai R.-Y. et al. 2015 PMID: 25253417, Orecchioni S. et al. 2015 PMID: 25196138,

Qian W. et al. 2018 PMID: 30053447

Target cancer stem cells and may help make them more vulnerable to standard cancer treatments

Saini et al. 2018. PMID: 29342230, Brown et al. 2020 PMID: 32369446,

Hirsch H.A. et al. 2009. PMID: 19752085, Scatena C. et al. 2018 PMID: 30364293,

Yang B. et al. 2015 PMID: 26111245, Bayat N. et al. 2016 PMID: 27836464,

Kato S. et al. 2018 PMID: 29848667, Kodach L.L. et al. 2011 PMID: 21551187,

Jiang W. et al. 2021. PMID: 34303383, vMarkowska A. et al. 2019 PMID: 31054863,

1 This table is a summary of some of the potential mechanisms of action reported for agents used in the COC Protocol as reported in the scientific literature. This is an evolving field of research, and this list is not exhaustive.