Project Details
Description
Clinical trials testing type 1 insulin-like growth factor receptor (IGF-1R) inhibitors failed in endocrine-
sensitive and resistant breast cancer. These trials failed to include targeting of the insulin receptor (IR)
and essential component of the IGF signaling system. Further, data from patients with endocrine resistant
breast cancer showed that insulin receptor (IR) is more highly expressed in breast cancer cells than IGF-
1R. While it may seem futile to target IR, data show the fetal isoform of IR, IR-A, is more highly
expressed than the adult isoform IR-B in cancers. Thus, it may be possible to create a cancer specific
inhibitor of a highly expressed receptor for breast cancer treatment.
We hypothesize that targeting of IR alone and in combination with other breast cancer therapeutics will
be an effective therapy. Moreover, specifically targeting IR-A will be cancer specific with little impact on
glucose homeostasis. To test this hypothesis, we propose three specific aims: 1) Engineer IR-A
antagonists using small synthetic protein ligands via directed evolution; 2) Demonstrate IR-A regulation
of the breast cancer malignant phenotype compared to IR-B and define a mechanism; and 3) Evaluate the
efficacy of an IR-A specific antagonist, our existing IR-A and IR-B antagonists, and IGF-1R antagonists
alone and in combination in breast cancer model systems
Major advances in breast cancer have been the direct result of understanding and targeting key growth
regulatory signals. Based on the failure of trials targeting the IGF-1R, we now have clear evidence that IR
play a critical role in breast cancer development. Just as we were at the among the first to develop IGF-1R
inhibitors, we have shown that IR inhibitors also may be used to target breast cancer. Completion of this
proposal will further the development of new targeted breast cancer therapies. Cancer specific IR may be
accomplished by development of an IR-A specific inhibitor. Given the growing number of women with
hyperinsulinemia, creating a cancer specific inhibitor of IR could have significant impact.
Status | Active |
---|---|
Effective start/end date | 6/1/20 → 5/31/24 |
Funding
- National Cancer Institute: $339,470.00
- National Cancer Institute: $347,385.00
- National Cancer Institute: $345,314.00
- National Cancer Institute: $339,048.00
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