MD position (w/m/d) - P13 Exploiting novel immune checkpoints in drug resistant lung tumors

Offer: MD Scholarship for doctoral thesis
Starting Date: 01.08.2024
Institute: DKTK Translational Oncology, Max-Lebsche-Platz 30 81377 München / LMU Klinikum, Marchioninistr. 15
Working Group: Interdisciplinary Research Collaboration Martin Sos (DKTK, Dept. Of Translational Oncology – Primary research site)/ Amanda Tufman (Pneumonology)

Research Topic: Exploiting novel immune checkpoints in drug resistant lung tumors

PROJECT DESCRIPTION

The advent of cancer genomics, revolutionized the molecular, clinical and phenotypical classification of virtually all tumors, including lung cancer as the deadliest and most aggressive tumor type. In parallel, we witnessed an unprecedented boost in the use of targeted agents involving the class of kinase inhibitors and more recently immunotherapies that helped to prolong the overall survival of molecularly defined tumors. The majority of immunotherapeutic agents that have been developed over the past years represent monoclonal antibodies that inhibit immunoregulatory proteins such as CTLA-4 or PD-L1 to boost the response of cytotoxic T cells.
Targeted kinase inhibitors on the other hand exploit genetically encoded dependencies expressed in tumor cells by enzymatically blocking signaling pathways that ensure cellular proliferation and survival. One of the most impactful findings on survival of lung cancer patients was the identification of EGFR mutations and their relevance for the activity of specific anti-EGFR drugs. Inspired by these findings we contributed to the identification of novel druggable cancer targets and to the development of novel therapeutic strategies to accelerate the efficacy of anti-cancer therapy. Nevertheless, in lung cancer patients and other solid tumor types even the most effective cancer therapy tailored against specific molecular dependencies is only transient. We and others have shown that virtually all patients receiving targeted therapy develop on-target resistance that prevents the binding of the drug or off-target resistance that overrides the inhibitory effects achieved by the treatment. However, emerging evidence suggests that before residual tumors become fully resistant unique vulnerabilities may arise in the drug tolerant cells. Interestingly, we recently identified B7-H4, a member of the B7 immune checkpoint family, as a surface protein expressed in the population of drug tolerant cells (Sos Lab; Brägelmann et al. Nat Commun 2021).
Here, we propose to use the commercially available antibody Alsevalimab developed to inhibit B7-H4 in genetically defined, patient-derived lung cancer models and to test its efficacy specifically in the context of resistance against tyrosine kinase inhibitors. In parallel, we will collect lung cancer specimen from patients that developed resistance against these drugs and use transcriptome and proteome analyses to characterize the role of B7-H4 in this setting. We expect to gain insight into the role of B7-H4 in the tumor microenvironment and to promote an innovative immunotherapeutic anti-cancer therapy. The doctoral thesis will be supervised by an interdisciplinary, translational committee including Prof. Martin Sos (DKTK Translational Oncology), Prof. Amanda Tufman (LMU Pulmonologist).

MANDATORY EVENTS

As holder of this scholarship you are a member of the Research Training Group (RTG) GRK 2338 “Targets in Toxicology”. The GRK represents a truly international program and benefits from an excellent scientific environment and a state-of-the-art research infrastructure.
As member of the RTG you have to participate in the lecture series “Toxicology of the lung” (once a month) and the annual Research Retreat (once a year). All other courses offered by the GRK can be attended optionally. For more information about the RTG GRK 2338 please visit the following website: https://www.grk2338.med.uni-muenchen.de/index.html

FUNDING

The scholarship will be given for 12 months, a minimum of 8 months full-time in the laboratory is required. The monthly scholarship payment is 1.037 €. In addition, a total amount of 395 € in lab consumables per month is available.

REQUIREMENTS

Medical student (LMU or TUM)

APPLICATION

If you want to apply for this scholarship, send an application (CV, project title, motivation letter and certificates) to S.Resenberger@lmu.de by 10th of May 2024. 

For project-specific questions please contact Prof. Dr. Martin Sos (martin.sos@dkfz-heidelberg.de).
Women and people from other underrepresented groups are strongly encouraged to apply and we will seek to provide any support you require to complete the project.