PIM kinase as a novel therapeutic target for triple-negative breast cancer

Project: Research project

Project Details

Description

The greatest clinical challenge in treating breast cancer occurs in those patients whose tumors lack expression of the estrogen and progesterone receptors as well as the HER2 oncoprotein. There is no targeted therapy that currently exists against this aggressive type of “triple negative” breast cancer (TNBC), and TNBC patients are currently treated with a combination of non-specific chemotherapy, radiation and surgery. This is in strict contrast to cases of tumors positive for the expression of hormone and HER2 receptors, for which less toxic, targeted therapies have been developed for clinical use (i.e., Herceptin for HER2+ tumors). The lack of such targeted therapies against TNBC is due to the fact that we know very little about how TNBC occurs and progresses to become lethal. We previously took computational approaches to analyze a large number of patient tumor samples and discovered that a highly potent cancer-causing gene called MYC was significantly activated in ~50% of all TNBC cases. Our findings were subsequently validated by The Cancer Genome Atlas (TCGA), the national effort to molecularly characterize the biology of breast cancer. Additionally, we found that elevated MYC activity was associated with poor clinical outcomes, suggesting that MYC uniquely contributes to the aggressiveness of TNBC. Yet, due to structural constraints, MYC cannot be directly inhibited with small molecule inhibitors. However, MYC-driven tumors are still able to be challenged. An alternate approach to directly inhibiting an undruggable target such as MYC is to find synthetic lethal combinations that selectively kill MYC-driven tumors without affecting healthy cells. The term “synthetic lethality” refers to a genetic context in which a mutation in a gene, which itself is not lethal, can cause lethality when combined with a mutation in another gene. Thus, in the case of MYC, we would like to establish a druggable target that is indispensable only in MYC-driven TNBC cells, but not in healthy cells. We have identified a promising target called PIM and have found that PIM co-exists with MYC in human TNBC samples, and that MYC-driven tumors are dependent on PIM to continuously grow in animals. What is promising about PIM is that PIM is not an essential gene, meaning that the level of potential cytotoxicity is expected to be very low. In fact, several pharmaceutical companies have already generated clinical PIM inhibitors which are being clinically evaluated against liquid tumor types such as leukemia. In this proposed research, we would like to expand our prior studies to establish PIM inhibition as a clinically relevant, novel and safe targeted therapy against MYC-driven TNBC. We hope that the successful completion of this proposed research will directly result in the initiation of early phase clinical studies.
StatusFinished
Effective start/end date8/31/168/30/19

Funding

  • Susan G. Komen Breast Cancer Foundation (CCR16376693)

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