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Apr 1 – 5, 2019
Fairmont Château Laurier Hotel
UTC timezone

IGF-1R Targeted Alpha Therapeutic FPI-1434 causes DNA double-stranded breaks and induces regression in preclinical models of human cancer

Not scheduled
Fairmont Château Laurier Hotel

Fairmont Château Laurier Hotel


Dr Natalie Grinshtein (Fusion Pharmaceuticals)


Objectives: Insulin-like growth factor-1 receptor (IGF-1R) is an oncogenic protein that is over-expressed in multiple solid tumors. IGF-1R targeted therapeutics have not demonstrated clinical efficacy for treating cancers either as stand-alone agents or in combination with other therapies. Despite this, targeted alpha therapeutic agents (TATs) may be ideal for treating IGF-1R expressing cancers due to their high potency and lower protein mass dose. Herewith we describe the preclinical efficacy of FPI-1434 in several solid tumor models and provide insight into its mechanism of action. Methods: FPI-1434 was produced by conjugating with a lysine directed bifunctional chelated to AVE1642 and radiolabeled with Ac-225. Single dose radiotherapeutic efficacy studies were carried out using Colo-205 (colorectal), A549 (radioresistant lung), or LNCaP (prostate) xenografts inoculated into immunodeficient mice. Animals received single doses ranging from 0.05 μCi to 0.4 μCi with a corresponding dose of total protein typically less than 10 μg (0.5 mg/kg). Study endpoints included tumor volume measurement and/or impact to animal health status. Results: Colo-205 xenograft bearing mice received single doses of FPI-1434 at 0.05, 0.2, and 0.4 μCi or vehicle and radiotherapeutic efficacy was followed for 178 days. FPI-1434 caused suppression of tumor growth at the 0.05 μCi dose and the 0.2 and 0.4 μCi doses caused durable tumor regression. In addition, FPI-1434 caused regression in large Colo-205 tumors grown to a volume of greater than 400 mm prior to dosing. FPI-1434 was also efficacious in the LNCaP and A549 models following single doses of radioimmunoconjugate. To elucidate the mechanism of action, COLO205 tumors treated with 400 nCi FPI-1434 were isolated at 24h, 96h and 168h post treatment, fixed, paraffin-embedded and stained with γH2AX (S139), a marker of double-stranded DNA breaks and Cleaved Caspase 3 (CC3), an early/intermediate apoptosis marker. γH2AX phosphorylation (S139) was almost undetectable at 24h but became more prominent at 96h and 168h post treatment. CC3 followed a similar pattern to yH2AX, highlighting cell nuclei actively undergoing apoptosis because of double-stranded DNA breaks. Current efforts are focusing on confirming the role of apoptosis and investigating the contribution of necrosis, autophagy and senescence to FPI-1434 mechanism of action. Conclusion: Single doses of FPI-1434 as a standalone agent in pre-clinical models demonstrate a high degree of durable anti-tumor efficacy in multiple tumor xenograft types. The mechanism of action involves induction of DNA double-stranded breaks and progression into apoptosis. These results strongly support the use of FPI-1434 in IGF-1R overexpressing cancers.
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Presentation Type Contributed Oral

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Dr Natalie Grinshtein (Fusion Pharmaceuticals)


Dr Eric Burak (Fusion Pharmaceuticals) Dr John Forbes (Fusion Pharmaceuticals) Prof. John Valliant (Fusion Pharmaceuticals) Dr Matthew Moran (Fusion Pharmaceuticals) Dr Meiduo Hu (Fusion Pharmaceuticals) Dr Ryan Simms (Fusion Pharmaceuticals) Mrs Yaryna Storozhuk (Fusion Pharmaceuticals)

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