From understanding to rational design of next-generation cancer therapies
Immunotherapy combined with cytotoxic and molecular therapies have entered centre stage as novel treatments for cancer. Despite this advance, toxicity and insufficient efficacy in many patients remain major obstacles and illustrat...
Immunotherapy combined with cytotoxic and molecular therapies have entered centre stage as novel treatments for cancer. Despite this advance, toxicity and insufficient efficacy in many patients remain major obstacles and illustrate the need for therapy improvement based on a deeper understanding of the cellular damage and repair responses to drugs and immunotherapy.
To overcome this roadblock, I propose a previously unappreciated approach by combining immunotherapy with cancer therapies at ultra-low, sublethal dose. We demonstrated that cytotoxic T cells induce sublethal membrane and DNA damage and oxidative stress which, when repaired, allows for tumor cell survival. However, when damage adds up, the tumor cell dies.
I hypothesize that sublethal effects reveal novel vulnerabilities in cancer cells which can be exploited by complementary multi-targeted therapies at ultra-low dose which are nontoxic individually but, when combined, achieve lethality by an additive mechanism.
Taking advantage of innovative microscopy, I aim to produce a catalogue of damages and repair types, and their combined effects in tumor cells. Single-cell analyses combined with advanced statistics and mathematical modeling will be used to derive the damage profile and duration of damage for each modality in tumor cells, yet without side effects towards immune effector cells. I will design algorithms for multi-targeted regimens to achieve additive damage, reduced repair, and death induction and validate them in immunotherapy models in vitro and in local and disseminated preclinical cancer in vivo. If resistance occurs, survival programs will be detected by single-cell transcriptomics and countered by orthogonal targeting.
subLETHAL will 1) identify sublethal damage as the basis of cytotoxic therapy, 2) enable rational design of multi-targeted ultra-low dose additive regimens and advance 3) the understanding, efficacy and tolerability of chemoimmunotherapy for 4) rapid clinical translation.ver más
Seleccionando "Aceptar todas las cookies" acepta el uso de cookies para ayudarnos a brindarle una mejor experiencia de usuario y para analizar el uso del sitio web. Al hacer clic en "Ajustar tus preferencias" puede elegir qué cookies permitir. Solo las cookies esenciales son necesarias para el correcto funcionamiento de nuestro sitio web y no se pueden rechazar.
Cookie settings
Nuestro sitio web almacena cuatro tipos de cookies. En cualquier momento puede elegir qué cookies acepta y cuáles rechaza. Puede obtener más información sobre qué son las cookies y qué tipos de cookies almacenamos en nuestra Política de cookies.
Son necesarias por razones técnicas. Sin ellas, este sitio web podría no funcionar correctamente.
Son necesarias para una funcionalidad específica en el sitio web. Sin ellos, algunas características pueden estar deshabilitadas.
Nos permite analizar el uso del sitio web y mejorar la experiencia del visitante.
Nos permite personalizar su experiencia y enviarle contenido y ofertas relevantes, en este sitio web y en otros sitios web.