Quinacrine and 5-fluorouracil treatment of primary colorectal tumor samples

• Grant number: 16/04446-1
• Support Opportunities: Scholarships abroad - Research Internship - Doctorate
• Start date: November 01, 2016
• End date: October 31, 2017
• Field of knowledge: Health Sciences - Medicine
• Principal Investigator: Bryan Eric Strauss
• Grantee: Paulo Roberto Del Valle
• Supervisor: Wafik S. El-Deiry
• Host Institution: Instituto do Câncer do Estado de São Paulo Octavio Frias de Oliveira (ICESP). Coordenadoria de Serviços de Saúde (CSS). Secretaria da Saúde (São Paulo - Estado). São Paulo , SP, Brazil
• Institution abroad: Fox Chase Cancer Center (FCCC), United States
• Associated to the scholarship: 13/16074-3 - P53/ARF and interferon-beta pathways as targets for colorectal carcinoma gene therapy, BP.DR

Abstract

Colorectal cancer remains a challenge despite recent advances in treatment. It is the third most common carcinoma and the second cause of cancer related death. There is a plethora of genetic alterations linked to development and progression of colorectal cancer, though these varied phenotypes are unified by disruption in the balance between tumor suppressor and oncogenic pathways, often involving p53. Since p53 plays a major role in inducing cell death, many have attempted to rescue p53 function via pharmacological approaches. Strikingly, quinacrine was shown to rescue p53 from proteosomal degradation and induce expression of target genes, including DR5. It was also observed that quinacrine can induce p53-dependent and independent cell death. In colorectal cancer, quinacrine was tested against a panel of 10 cell lines, showing a potent cytostatic effect in vitro and in vivo, with inhibition of NFkB. Moreover, quinacrine synergizes with 5-fluorouracil (5-FU), a standard treatment for colorectal cancer, resulting in significantly increased levels of cell death. However, much remains to be revealed about the molecular mechanisms of synergy of quinacrine and 5-FU. For example, this drug combination has not yet been tested in organoid models and in primary samples, possibly revealing the induction of immunogenic cell death in a clinically relevant model. Thus we propose the evaluation of primary, patient-derived colorectal cancer cells upon treatment with 5-FU plus quinacrine, in vitro and in vivo, with the aim of revealing key mediators of the cellular response. (AU)