title: Targeted delivery of chemotherapy using HSP90 inhibitor drug conjugates is highly active against pancreatic cancer models.
abstract: 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.
authors: Program in Molecular Therapeutics, Fox Chase Cancer Center, Philadelphia, PA, USA.
authors: Egor
authors: E
authors: Bobrov
authors: Program in Molecular Therapeutics, Fox Chase Cancer Center, Philadelphia, PA, USA.
authors: Natalia
authors: N
authors: Skobeleva
authors: Program in Molecular Therapeutics, Fox Chase Cancer Center, Philadelphia, PA, USA.
authors: Diana
authors: D
authors: Restifo
authors: Program in Molecular Therapeutics, Fox Chase Cancer Center, Philadelphia, PA, USA.
authors: Natalya
authors: N
authors: Beglyarova
authors: Histopathology Facility, Fox Chase Cancer Center, Philadelphia, PA, USA.
authors: Kathy Q
authors: KQ
authors: Cai
authors: Biostatistics and Bioinformatics Facility, Fox Chase Cancer Center, Philadelphia, PA, USA.
authors: Elizabeth
authors: E
authors: Handorf
authors: Immune Cell Development and Host Defense Program, Fox Chase Cancer Center, Philadelphia, PA, USA.
authors: Kerry
authors: K
authors: Campbell
authors: Synta Pharmaceuticals, Lexington, MA, USA.
authors: David A
authors: DA
authors: Proia
authors: Nexus Pharma, Langhorne, PA, USA.
authors: Vladimir
authors: V
authors: Khazak
authors: Program in Molecular Therapeutics, Fox Chase Cancer Center, Philadelphia, PA, USA.
authors: Erica A
authors: EA
authors: Golemis
authors: Program in Molecular Therapeutics, Fox Chase Cancer Center, Philadelphia, PA, USA.
authors: Igor
authors: I
authors: Astsaturov
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000494:pharmacology; D002166:Camptothecin / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D021441:Carcinoma, Pancreatic Ductal / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D004249:DNA Damage; D006801:Humans; D051379:Mice; D058990:Molecular Targeted Therapy; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics; D012118:Resorcinols / Q000008:administration & dosage* / Q000494:pharmacology; D016159:Tumor Suppressor Protein p53 / Q000235:genetics; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D012118:Resorcinols; C000610389:STA-12-8666; D016159:Tumor Suppressor Protein p53; C495971:Hras protein, mouse; D016283:Proto-Oncogene Proteins p21(ras); D002166:Camptothecin
keywords: HSP90i drug conjugate; KPC mouse model; SN-38; pancreatic cancer; patient-derived xenografts