PROJECT SUMMARY: This application is being submitted in response to the Notice of Special Interest (NOSI) identified as NOT-CA- 21-009 to establish a collaboration between the parent 1 R01 CA241148-01A1 and the NCI-supported PDX Development and Trial Centers Research Network (PDXNet)-Wistar Institute site. The project focuses on a unique form of cancer cell drug resistance identified in the parent R01 mediated by the Aldehyde Dehydrogenase (ALDH) expressing cellular subpopulations present in tumors. The ALDH family of enzymes convert toxic aldehydes generated during cellular metabolism into corresponding less toxic carboxylic acids that can be excreted and removed. ALDH expression and activity increases during tumor progression with a corresponding higher positive (ALDH+) subpopulation. In the parent R01, we have found that changing the size of the ALDH+ and negative (ALDH-) cell subpopulations, which occurs during drug treatment and resistance development, performs an important role in maintaining tumor ROS levels in an optimal range needed for the development of this novel type of drug resistance. This supplement proposes a collaboration to use melanoma PDXs developed by Dr. Meenhard Herlyn at the Wistar Institute to identify the most effective approach to prevent this novel form of cancer cell resistance. The goal will be to target the ALDH+ cells using DIMATE (under clinical evaluation for leukemia) in combination with a clinically used BRAF and MEK inhibitor combination targeting the ALDH- subpopulation. The evaluation would be undertaken in PDX models naïve or resistant to the BRAF/MEK drug combination. In the parent R01, we have discovered that ALDH+ and ALDH- cell subpopulations, cooperate to promote survival and achieve drug resistance. Furthermore, we have discovered in cultured cell line-based models that this cooperation can best be prevented by therapeutically targeting both populations. The ALDH cell number and/or the related ROS pathway signaling can be used as biomarkers to assess treatment efficacy in the PDX models. Therefore, we have formulated a novel central hypothesis that drug resistance can be prevented in cancer by targeting the ALDH positive cell population with DIMATE and the negative population by targeting the MAP kinase pathways through BRAF and MEK inhibition in PDX tumors resistant to MAP kinase inhibition. To test this hypothesis, we will determine the most effective consecutive or simultaneous targeting approach to prevent resistance in PDX melanoma models naïve or resistant to BRAF/MEK inhibition using DIMATE. PDX models used would have developed resistant to MAP kinase pathway inhibition through different mechanisms. The effectiveness of DIMATE will be compared to nanoKS100 (a preclinical agent developed in the Parent R01 Award), which we have found is effective at preventing resistance when combined with MAP kinase pathway targeting. The clinical significance of this project is that if successful, these discoveries could provide a solid rationale for testing this approach in the clinic.
|Effective start/end date||4/1/21 → 3/31/22|
- National Cancer Institute: $628,206.00
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