Conference Paper

Abstract P1-21-05: A novel long-acting insulin for cancer therapy reduces xenograft tumor growth

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A link between obesity, metabolic dysfunction, and an increased risk in cancer mortality has been well established in several cancer types including, breast, colon, pancreatic, and prostate cancers. A likely mechanism driving this elevated risk is the associated increase in circulating insulin and insulin-like growth factor (IGF), which are known promoters of cancer growth and have been linked to shorter progression-free survival, and increased risk of metastatic disease and death in breast cancer patients. IGF receptor (IGF1R) targeting has been unsuccessful as insulin receptor (IR) also is functional in breast cancers. To address IR targeting, Akston Biosciences developed a novel insulin-Fc fusion protein (AKS-130) with the goal of lowering patient blood glucose levels without causing clinical hypoglycemia. AKS-130 was also found to downregulate IR expression in models of colon cancer (HCT-116) and malignant melanoma (WM266.4). Further, AKS-130 suppressed xenograft growth in fed and fasted states. We examined if AKS-130 had similar effects on estrogen receptor (ER) positive breast cancer cells as ER+ breast cancers may have elevated expression or activation of IGF1R and IR. Data from our lab show that development of endocrine therapy resistance in ER+ breast cancer cell lines is associated with loss of IGF1R expression and subsequently increased sensitivity to insulin signaling, which supports overlapping pro-tumorigenic signaling pathways to IGF1R. To test the hypothesis that resistance to endocrine therapy increases the reliance of ER+ breast cancer cells on IR signaling, we used the ER+ breast cancer cell line, MCF-7L, and a Tam resistant derivative, MCF-7L TamR, to assess IR/IGF1R activation and growth in response to AKS-130. Similar to HCT-116 and WM266.4 cells, MCF-7L parental and TamR cells showed that AKS-130 was an agonist of IR. But after 72 hours of exposure, a marked reduction in IR was seen and associated with partially suppressed downstream signaling to Akt. Interestingly, AKS-130 induced proliferation at similar levels to insulin treatment in MCF-7L parental cells at three and five days post treatment. However, pre-treatment of cells with AKS-130 suppressed further insulin-stimulated growth in MCF-7L TamR cells. Ongoing studies are evaluating the effects of AKS-130 on ER+ breast cancer xenografts to determine if the ability of the drug to downregulate IR expression results in decreased tumor growth. Taken together these data show that novel agents, such as AKS-130, can target IR function in cancer cells. AKS-130 is a drug which may serve as way to disrupt IR in cancer cells without affecting host glucose metabolism. Targeting of IR signaling may represent a new strategy to overcome endocrine therapy resistance in breast cancer. Citation Format: Lynsey M Fettig, Xihong Zhang, Kelly LaPara, Sylaja Murikipudi, Andrea R Delpero, Thomas M Lancaster, Todd C Zion, Douglas Yee. A novel long-acting insulin for cancer therapy reduces xenograft tumor growth [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P1-21-05.

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... In accordance, our data indicate that AKS-130 downregulates IR and partially blocks PI3K/Akt signaling in both MCF-7L and Tamoxifen-resistant (TamR) MCF-7L cells. Additionally, AKS-130 inhibits insulin-stimulated growth in TamR MCF-7L cells [97]. However, the in vivo effects of AKS-130 and the binding preference for different IR-isoform are still unknown. ...
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The insulin and insulin-like growth factor (IGF) system plays an important role in regulating normal cell proliferation and survival. However, the IGF system is also implicated in many malignancies, including breast cancer. Preclinical studies indicate several IGF blocking approaches, such as monoclonal antibodies and tyrosine kinase inhibitors, have promising therapeutic potential for treating diseases. Uniformly, phase III clinical trials have not shown the benefit of blocking IGF signaling compared to standard of care arms. Clinical and laboratory data argue that targeting Type I IGF receptor (IGF1R) alone may be insufficient to disrupt this pathway as the insulin receptor (IR) may also be a relevant cancer target. Here, we review the well-studied role of the IGF system in regulating malignancies, the limitations on the current strategies of blocking the IGF system in cancer, and the potential future directions for targeting the IGF system.
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