> Our Work > The Work We Fund

2022 CRIS Cancer Foundation, Eustace Wolfington and Larry Leeds – PCF Young Investigator Award

Exploring Synthetic Lethality of Targeting miR346-Unfolded Protein Response Dependent DNA Damage Response Mechanisms in Treatment-Resistant Prostate Cancer

Dimitrios Doultsinos , PhD
University of Oxford

Mentors: Claire Fletcher, PhD, Ian Mills, PhD

Description:

  • Cancer cells exhibit rapid proliferation, which is supported by altered metabolism and demand for greater rates of protein and nucleic acid synthesis. However, as expected for a production line, faster rates of protein generation may lead to greater numbers of mistakes in the “end product” protein structure. Accumulation of such erroneous proteins trigger stress signals that if not resolved may lead to cell death. To avoid death, cancer cells employ altered stress detection and response pathways.
  • The unfolded protein response is one such pathway that senses stress caused by high levels of mis-folded proteins and reduces the rates of protein synthesis by governing processes like ERAD (protein clearance), metabolic rate and mRNA/miRNA cleavage.
  • Dr. Dimitrios Doultsinos is investigating the biology of the unfolded protein response in prostate cancer, focusing on the roles of pathway regulators IRE1 and XBP1 as well as miR-346, a miRNA that has been shown to have clinical significance in prostate cancer as well as biological links to the unfolded protein response.
  • In this project, Dr. Doultsinos will evaluate the biologic mechanisms by which IRE1, XBP1, and miR-346 synergize to coordinate stress responses to DNA damage.
  • Whether targeting these factors may have therapeutic potential alone or in combination with other prostate cancer treatments will be evaluated in preclinical prostate cancer models.
  • If successful, this project will uncover a new biology of prostate cancer and may lead to the development of new biomarkers and treatments that may be particularly relevant for patients with alterations in DNA damage repair pathways.

What this means to patients: Altered stress response pathways are a hallmark of cancer which allows tumor cells to rapidly grow and avoid normal death signals; however, these alterations may also create sensitivities that can be therapeutically targeted. Dr. Doultsinos will determine the biology of the unfolded protein response in prostate cancer and determine whether these alterations may act as biomarkers for sensitivity to certain treatments, or may be promising therapeutic targets themselves.