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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:IntroductionMetastatic pancreatic ductal adenocarcinoma (mPDAC) is a common cancer with poor survival outcomes. Although treatment options are limited, real-world treatment patterns and outcomes are not well understood, particularly beyond first-line treatment. This study described real-world treatment patterns and outcomes for mPDAC in the USA.MethodsThis retrospective analysis used electronic health record-derived de-identified data of patients with mPDAC diagnosed between January 1, 2014 and June 30, 2021. Treatments were classified into six groups: (1) standard combination chemotherapy; (2) nonstandard combination chemotherapy; (3) single-agent chemotherapy; (4) targeted therapy; (5) clinical study drugs; and (6) off-label therapies. Analyses were descriptive in nature. Treatment utilization and switching, and time on treatment and time to discontinuation, were described by first-line (1LOT) and second-line (2LOT) treatment groups. Median overall survival (mOS) from 1LOT and 2LOT was stratified by treatment group, and for 1LOT on the basis of whether patients received further treatment.Results1LOT included 6979 patients, 3241 (46%) of whom received further 2LOT. Standard combination chemotherapy was the most common 1LOT (70%) and 2LOT (46%). Nonstandard combination chemotherapy was used more as 2LOT (35%) than 1LOT (11%). First-line time on treatment was generally higher than second-line time on treatment, and time to discontinuation was lower than time on treatment. mOS in days (months) from 1LOT was 271 (8.9), 252 (8.3), 219 (7.2), 170 (5.6), 280 (9.2), and 182 (6.0), and mOS from 2LOT was 202 (6.6), 193 (6.3), 186 (6.1), 193 (6.3), 179 (5.9), and 97 (3.2), for groups 1-6, respectively. Within group 1, mOS from 1LOT was 318 days (10.4 months) for FOLFIRINOX and 241 days (7.9 months) for gemcitabine and nab-paclitaxel.ConclusionMost patients with mPDAC received 1LOT in line with clinical practice guidelines, yet mOS remains poor. This study highlights the need for novel therapies to demonstrate improved patient survival compared with therapies in current clinical practice guidelines.

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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