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Tailored first-line and second-line CDK4-targeting treatment combinations in mouse models of pancreatic cancer.

ABSTRACT: OBJECTIVE:Extensive molecular heterogeneity of pancreatic ductal adenocarcinoma (PDA), few effective therapies and high mortality make this disease a prime model for advancing development of tailored therapies. The p16-cyclin D-cyclin-dependent kinase 4/6-retinoblastoma (RB) protein (CDK4) pathway, regulator of cell proliferation, is deregulated in PDA. Our aim was to develop a novel personalised treatment strategy for PDA based on targeting CDK4. DESIGN:Sensitivity to potent CDK4/6 inhibitor PD-0332991 (palbociclib) was correlated to protein and genomic data in 19 primary patient-derived PDA lines to identify biomarkers of response. In vivo efficacy of PD-0332991 and combination therapies was determined in subcutaneous, intrasplenic and orthotopic tumour models derived from genome-sequenced patient specimens and genetically engineered model. Mechanistically, monotherapy and combination therapy were investigated in the context of tumour cell and extracellular matrix (ECM) signalling. Prognostic relevance of companion biomarker, RB protein, was evaluated and validated in independent PDA patient cohorts (>500 specimens). RESULTS:Subtype-specific in vivo efficacy of PD-0332991-based therapy was for the first time observed at multiple stages of PDA progression: primary tumour growth, recurrence (second-line therapy) and metastatic setting and may potentially be guided by a simple biomarker (RB protein). PD-0332991 significantly disrupted surrounding ECM organisation, leading to increased quiescence, apoptosis, improved chemosensitivity, decreased invasion, metastatic spread and PDA progression in vivo. RB protein is prevalent in primary operable and metastatic PDA and may present a promising predictive biomarker to guide this therapeutic approach. CONCLUSION:This study demonstrates the promise of CDK4 inhibition in PDA over standard therapy when applied in a molecular subtype-specific context.

SUBMITTER: Chou A

PROVIDER: S-EPMC6241608 | biostudies-literature | 2018 Dec

REPOSITORIES: biostudies-literature

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Tailored first-line and second-line CDK4-targeting treatment combinations in mouse models of pancreatic cancer.

Chou Angela A Froio Danielle D Nagrial Adnan M AM Parkin Ashleigh A Murphy Kendelle J KJ Murphy Kendelle J KJ Chin Venessa T VT Wohl Dalia D Steinmann Angela A Stark Rhys R Drury Alison A Walters Stacey N SN Vennin Claire C Burgess Andrew A Pinese Mark M Chantrill Lorraine A LA Cowley Mark J MJ Molloy Timothy J TJ Waddell Nicola N Johns Amber A Grimmond Sean M SM Chang David K DK Biankin Andrew V AV Sansom Owen J OJ Morton Jennifer P JP Grey Shane T ST Cox Thomas R TR Turchini John J Samra Jaswinder J Clarke Stephen J SJ Timpson Paul P Gill Anthony J AJ Pajic Marina M

Gut 20171028 12

<h4>Objective</h4>Extensive molecular heterogeneity of pancreatic ductal adenocarcinoma (PDA), few effective therapies and high mortality make this disease a prime model for advancing development of tailored therapies. The p16-cyclin D-cyclin-dependent kinase 4/6-retinoblastoma (RB) protein (CDK4) pathway, regulator of cell proliferation, is deregulated in PDA. Our aim was to develop a novel personalised treatment strategy for PDA based on targeting CDK4.<h4>Design</h4>Sensitivity to potent CDK4 ...[more]

PMID: 29080858

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Project description:INTRODUCTION:We recently validated monoclonal antibody (mAb) 376.96 as an effective carrier for targeted ?-particle radioimmunotherapy (RIT) with 212Pb in ovarian cancer mouse models. In this study, we tested the binding of radiolabeled mAb 376.96 to human pancreatic ductal adenocarcinoma (PDAC) cells and localization in xenografts in immune-deficient mice and evaluated 212Pb-labeled 376.96 (212Pb-376.96) for PDAC therapy. METHODS:In vitro Scatchard assays assessed the specific binding of 212Pb-376.96 to human PDAC3 adherent differentiated cells and non-adherent cancer initiating cells (CICs) dissociated from tumorspheres. In vitro clonogenic assays were used to measure the proliferation of adherent PDAC3 cells and CIC-enriched tumorspheres treated with 212Pb-376.96 or the irrelevant isotype-matched 212Pb-F3-C25. Mice bearing patient derived pancreatic cancer Panc039 xenografts were i.v. injected with 0.17-0.70?MBq 212Pb-376.96 or isotype control 212Pb-F3-C25, and used for biodistribution and tumor growth inhibition studies. Mice bearing orthotopic PDAC3 xenografts were i.v. co-injected with 99mTc-376.96 and 125I-F3-C25 and used for biodistribution studies. RESULTS:212Pb-376.96 specifically bound to PDAC3 adherent and dissociated tumorsphere CICs; Kd values averaged 9.0 and 21.7?nM, respectively, with 104-105?binding?sites/cell. 212Pb-376.96 inhibited the clonogenic survival of PDAC3 cells or CICs dissociated from tumorspheres 3-6 times more effectively than isotype-matched control 212Pb-F3-C25. Panc039 s.c. tumors showed significantly higher uptake of 212Pb-376.96 (14.0?±?2.1% ID/g) compared to 212Pb-F3-C25 (6.5?±?0.9% ID/g, p?<?.001) at 24?h after dosing. Orthotopic PDAC3 tumors showed significantly higher uptake of 99mTc-376.96 (6.4?±?1.8% ID/g) compared to 125I-F3-C25 (3.9?±?0.9% ID/g, p?<?.05) at 24?h after dosing. Panc039 tumor growth was significantly inhibited by 212Pb-376.96 compared to 212Pb-F3-C25 or non-treated control tumors (p?<?.05). CONCLUSION:Our results provide evidence for the efficacy of B7-H3 targeted RIT against preclinical models of pancreatic ductal adenocarcinoma (PDAC) and support future studies with 212Pb-376.96 in combination with chemotherapy to potentiate efficacy against PDAC.

Project description:PURPOSE:Lung cancer is one of the most common types of cancer, resulting in approximately 1.8 million deaths worldwide. Immunotherapy using checkpoint inhibitors has become standard of care in advanced non-small cell lung cancer (NSCLC), and there is increasing interest in further improving outcomes through combination with other therapeutics. This systematic review evaluates emerging phase III data on the efficacy and safety of checkpoint inhibitor combinations as first-line treatment for advanced NSCLC. MATERIALS AND METHODS:Published and presented literature was searched using the key search terms "non-small cell lung cancer" AND "checkpoint-inhibitors" (OR respective aliases) AND phase III trials. Seven randomized phase III clinical trials reporting outcomes on checkpoint inhibitor combinations in first-line advanced NSCLC were identified. RESULTS:Four first-line trials reported outcomes for checkpoint inhibitor combinations in nonsquamous NSCLC. Pembrolizumab-chemotherapy, atezolizumab-chemotherapy, and atezolizumab-bevacizumab-chemotherapy showed significantly improved overall survival compared with controls in patients with advanced nonsquamous epidermal growth factor receptor-negative (EGFR-)/ anaplastic lymphoma kinase gene (ALK)- NSCLC. Two trials reported outcomes for squamous NSCLC, with pembrolizumab-chemotherapy reporting significantly improved overall survival (OS) compared with chemotherapy. The combination of nivolumab-ipilimumab in all-comer histology failed to improve OS compared with histology appropriate chemotherapy in patients regardless of their tumor mutational burden status. Based on improved survival and safety, either pembrolizumab monotherapy or pembrolizumab-chemotherapy administered based on PD-L1 status and histology is a preferred treatment option. Outcomes for atezolizumab-bevacizumab-chemotherapy in EGFR+/ALK+ patients are promising and require further exploration. CONCLUSION:First-line checkpoint inhibitors added to standard therapies improve overall survival for nonsquamous EGFR-/ALK- and squamous advanced NSCLC. IMPLICATIONS FOR PRACTICE:Single-agent immune checkpoint inhibitors are now standard of care for advanced non-small cell lung cancer (NSCLC), and emerging data show that combining these agents with established chemotherapy further improves outcomes. The phase III KEYNOTE-189 and IMPower-130 trials showed significantly improved survival using this strategy for nonsquamous NSCLC, and the phase III KEYNOTE-407 trial showed similar results in squamous disease. Checkpoint inhibitor combinations are therefore an important new treatment option for first-line NSCLC. Programmed death ligand-1 expression may inform the use of checkpoint inhibitor combination therapy, and overall tumor mutation burden is also an emerging biomarker for this new treatment strategy.

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Tailored first-line and second-line CDK4-targeting treatment combinations in mouse models of pancreatic cancer.

Publications

Tailored first-line and second-line CDK4-targeting treatment combinations in mouse models of pancreatic cancer.

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