Targeted delivery of chemotherapy using HSP90 inhibitor drug conjugates is highly active against pancreatic cancer models
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Egor Bobrov1, Natalia Skobeleva1, Diana Restifo1, Natalya Beglyarova1, Kathy Q. Cai2, Elizabeth Handorf3, Kerry Campbell4, David A. Proia5, Vladimir Khazak6, Erica A. Golemis1, Igor Astsaturov1
1Program in Molecular Therapeutics, Fox Chase Cancer Center, Philadelphia, PA, USA
2Histopathology Facility, Fox Chase Cancer Center, Philadelphia, PA, USA
3Biostatistics and Bioinformatics Facility, Fox Chase Cancer Center, Philadelphia, PA, USA
4Immune Cell Development and Host Defense Program, Fox Chase Cancer Center, Philadelphia, PA, USA
5Synta Pharmaceuticals, Lexington, MA, USA
6Nexus Pharma, Langhorne, PA, USA
Igor Astsaturov, email: [email protected]
Keywords: HSP90i drug conjugate, Pancreatic cancer, patient-derived xenografts, SN-38, KPC mouse model
Received: June 16, 2016 Accepted: September 19, 2016 Published: October 13, 2016
The lack of effective treatment modalities is a major problem in pancreatic cancer (PCa), a devastating malignancy that is nearly universally driven by the “undruggable” KRAS and TP53 cancer genes. Poor tumor tissue penetration is the major source of resistance in pancreatic cancer where chemotherapy is the mainstay of treatment. In this study we exploited the selective tumor-targeting properties of the heat shock 90 protein inhibitors as the vehicle for drug delivery to pancreatic tumor tissues. STA-12-8666 is a novel esterase-cleavable conjugate of an HSP90i and a topoisomerase I inhibitor, SN-38. STA-12-8666 selectively binds activated HSP90 and releases its cytotoxic payload resulting in drug accumulation in pancreatic cancer cells in vivo. We investigated the preclinical activity of STA-12-8666 in patient derived xenograft and genetic models of pancreatic cancer.
Treatment with STA-12-8666 of the KPC mice (knock-in alleles of LSL-KrasG12D, Tp53fl/fl and Pdx1-Cre transgene) at the advanced stages of pancreatic tumors doubled their survival (49 days vs. 74 days, p=0.008). STA-12-8666 also demonstrated dramatically superior activity in comparison to equimolar doses of irinotecan against 5 patient-derived pancreatic adenocarcinoma xenografts with prolonged remissions in some tumors. Analysis of activity of STA-12-8666 against tumor tissues and matched cell lines demonstrated prolonged accumulation and release of cytotoxic payload in the tumor leading to DNA damage response and cell cycle arrest.
Our results provide a proof-of-principle validation that HSP90i-based drug conjugates can overcome the notorious treatment resistance by utilizing the inherently high affinity of pancreatic cancer cells to HSP90 antagonists.
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