pTyr-SNV for Personalized Medicine

Project:  pTyr-SNV as Targets for Personalized Medicine

Descriptive Title: Germline variants altering membrane-proximal phosphotyrosine signaling motifs as predictive markers for personalized cancer treatment

Introduction:

Cancer remains one of the leading causes of death globally, and despite advances in treatment, the search for improving the effectiveness of cancer therapies continues. The identification of somatic mutations that affect tyrosine phosphorylation has provided important insights into cancer pathogenesis mechanisms. This knowledge has led to the development of tyrosine kinase inhibitors (TKIs) as drugs of choice for many cancer types. Germline variants, specifically non-synonymous single nucleotide variants (nsSNVs) that alter phosphotyrosine signaling motifs (pTyr-motifs) aka pTyr-SNVs (Ulaganathan VK, J Genet Genomics. 2023, Ulaganathan VK, Sci Rep 2020) are associated with cancer progression (Ulaganathan et al, Nature 2015) and reduced CD8 T cell infiltration in the tumor environment (Kogan et al, JCI 2018). In our upcoming research projects, we posit that pTyr-SNVs contribute to patient-to-patient variability in TKI therapy responsiveness or therapy-induced toxicity. Germline nsSNVs that impact membrane-proximal pTyr-motifs may also alter proximal signaling in cancer-fighting immune cells. Thus, patient-intrinsic pTyr-SNVs are very likely contributing to the variability in responsiveness to immune checkpoint blockade (ICB) therapies. However, it is unknown if pTyr-SNVs are associated with either TKI or ICB therapy responses. This project will attempt to fill this gap in our knowledge and answer the question of whether pTyr-SNVs can serve as the next generation of predictive markers for personalized cancer treatment.

Purpose:

The overarching goal is to identify patient-intrinsic pTyr-SNVs that are associated with better therapeutic outcomes or therapy-induced toxicities in various cancers. The ultimate goal is to discover clinically relevant pTyr-SNVs that can be used to stratify cancer patients for personalized treatments.

Objectives:

To discover patient-intrinsic pTyr-SNVs that are associated with the following traits:

    1. sensitive or resistant to TKI drugs

    2. sensitive or resistant to ICB drugs

    3. drug-induced toxicities

Methods:

Next generation sequencing technologies will be used to identify pTyr-SNVs in the germline exomes of cancer patients associated with therapy responsiveness. To validate the mechanistic basis of genetic association and identify potential candidate variants for clinical studies, cell line and animal models will be used. All preclinical studies can be carried out using standard biochemistry and molecular biology techniques, such as flow cytometry, imaging techniques, and functional assays.

Expected Outcomes:

Discovery of novel genetic biomarkers for stratifying cancer patients for personalized cancer treatments

References:

    1. Ulaganathan VK*., Vasileva M., A strategy for uncovering germline variants altering anti-tumour CD8 T cell response (2023) J Genet Genomics. Jan 20:S1673-8527(23)00002-4. doi: 10.1016/j.jgg.2023.01.001.
    2. Ulaganathan VK*., Membrane Anchorage-Induced (MAGIC) Knockdown of Non-synonymous Point Mutations (2022) Chembiochem. Jun 3. doi: 10.1002/cbic.202100637. 
    3. Ulaganathan VK*., TraPS-VarI: Identifying genetic variants altering phosphotyrosine based signalling motifs (2020) Sci Rep. May 21. doi: 10.1038/s41598-020-65146-2.
    4. Kogan D, Grabner A, Yanucil C, Faul C, Ulaganathan VK*., STAT3-enhancing germline mutations contribute to tumor-extrinsic immune evasion (2018) J Clin Invest. 2018 May 1. doi: 10.1172/JCI96708.
    5. Ulaganathan VK*, Ullrich A*., Membrane-proximal binding of STAT3 revealed by cancer-associated receptor variants (2016) Mol Cell Oncol. Feb 24. doi: 10.1080/23723556.2016.1145176.
    6. Ulaganathan VK*, Sperl B, Rapp UR, Ullrich A*., Germline variant FGFR4  p.G388R exposes a membrane-proximal STAT3 binding site (2015) Nature. Dec 24. doi: 10.1038/nature16449.

* Corresponding Author

Klaus Tschira Boost Fund Proposal 2023