I-Corps: Translation potential of mRNA lipid nanoparticles to inhibit tumor DNA damage tolerance

This I-Corps project is based on the development of a targeted cancer therapy designed to help existing cancer treatments work better and delay the onset of cancer drug resistance. Resistance to chemotherapy is a leading cause of relapse for cancer patients with advanced solid tumors. However, chemotherapy remains the backbone of treatment across many of these cancers, which creates a need for treatments that improve the performance of medicines already used in routine clinical practice. This technology is an add-on therapy given alongside standard chemotherapy to make tumor cells more vulnerable to chemotherapy treatment and reduces the emergence of resistant disease. It offers a low-disruption adoption path and a broad addressable opportunity spanning multiple types of cancers rather than a single indication as it is a complement to drugs already in widespread use. If successful, this approach may extend drug response durability, reduce treatment of recurrent disease, and enable partnerships with biopharmaceutical companies seeking to strengthen existing chemotherapies. This may provide more effective cancer treatment options for clinicians and improve patient outcomes. This I-Corps project utilizes experiential learning coupled with first-hand investigation of the industry ecosystem to assess the translation potential of an mRNA lipid nanoparticle to be used to enhance the efficacy of chemotherapeutic drugs. This technology is based on the transient expression of a dominant inhibitory protein targeting the DNA damage tolerance pathway in tumor cells. DNA damage tolerance, including translesion synthesis, allows cancer cells to keep replicating despite chemotherapy-induced DNA lesions and is a key driver of treatment failure and acquired cancer cell resistance. This mechanism is biologically distinct from classical DNA repair and has been difficult to block with conventional small molecules because it relies on complex intracellular protein-protein interactions. Preclinical studies show that this mRNA-based approach can sensitize tumor models to DNA-damaging chemotherapy with encouraging initial tolerability. The use of transient mRNA delivery to access a hard-to-drug intracellular survival mechanism may enable a potential new class of adjunctive cancer therapeutics that strengthen existing chemotherapy treatments rather than replace them. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.