Přehled
Doctoral study program: Biomedical Sciences
Form: doctoral (present)
Department: Department of Biology
Supervisor: Zdenek Andrysik, Ph.D.
Ph.D. position:
Overcoming resistance in tumor subpopulations treated with MDM2 and ISR inhibitors
Annotation:
TP53 is recognized as the most frequently mutated tumor suppressor gene in human cancers. The
p53 protein functions as a transcription factor that controls several cellular programs constraining cancer
progression, including cell cycle arrest, senescence, and apoptosis. However, in most cancer cell types,
targeted activation of p53 by small molecule inhibitors of its endogenous repressor MDM2 is insufficient
for triggering apoptosis. Therefore, investigating the mechanisms controlling cell fate choice upon p53
activation could illuminate strategies to overcome this critical shortcoming of p53-based cancer
monotherapies.
Within this context, we recently discovered a negative feedback mechanism whereby p53
activation inhibits the Integrated Stress Response (ISR) and restrains the apoptotic branch of the p53
network. These findings allowed us to design an innovative combinatorial treatment strategy and
demonstrate that targeted pharmacological induction of the ISR enhances activity of the p53 network,
leads to rapid apoptosis in cancer lines resistant to MDM2 inhibitors, and results in tumor growth arrest
in vivo. The overall goal of this project is to improve tumor response to the combined induction of p53
and ISR through two complementary approaches focused on potentiating the apoptotic response in
resistant tumor subpopulations.
First, we will develop a reporter system for monitoring and optimizing p53/ISR pharmacological
induction in vivo. Efficiencies of both p53- and ISR-activating drugs in vivo differ greatly, and efficacy
information for CRC treatments is limited. We hypothesize that bioavailability of MDM2 and eIF2a
inhibitors and their respective CRC-specific efficiencies are variable. Therefore, we propose to examine
p53/ISR activities in orthotopic CRC xenograft tumors following oral administration of 3-4 leading
compounds from each group using a fluorescence reporter system, as activities of both pathways can be
monitored easily at the transcription level. Specifically, we will generate a reporter system for both
monitoring tumor growth and activation of p53 and ATF4. We will test the system in vitro, implant
reporter-expressing organoids in mouse cecum, and identify the most efficacious MDM2/eIF2a inhibitors
for in vivo CRC tumor treatment.
Second, we will test strategies for overcoming treatment resistance in tumor subpopulations. Our
preliminary data revealed variable p53/ISR induction throughout the tumor. We hypothesize that
treatment-resistant subpopulations of tumor cells can be targeted pharmacologically to elicit strong
p53/ISR activation triggering apoptosis. Therefore, we will use spatial transcriptomics data from CRC
tumors to rank subpopulations based on p53/ISR activity. Next, we will identify druggable targets in cells
with low p53/ISR scores and validate top sensitizing strategies in vivo.
Funding of the research:
State external sources of PhD position funding
Information on funding PGS positions:
The program requires that all PhD students have some means of financial support of min. 25 000 CZK per month. This is often a combination of various sources (grants, scholarship etc.)
Requirements for the student according to the Doctoral Board:
The student’s minimum publication activity within the course of study is one first-author publication with an IF value above the median in the field or 2 first-author publications in journals with an IF value in the 3rd quartile in the field (Q3). A condition for successful completion of the studies is also a foreign internship of at least 1 month, which is an inseparable part of the studies. As part of their studies, students will also participate in the teaching.
Information about supervisor:
https://biology.med.muni.cz/en/research/zdenek-andrysik/about
