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Utilizing High Resolution Ultrasound to Monitor Tumor Onset and Growth in Genetically Engineered Pancreatic Cancer Models
Published on: April 7, 2018
Tailored first-line and second-line CDK4-targeting treatment combinations in mouse models of pancreatic cancer
Angela Chou1,2,3, Danielle Froio1, Adnan M Nagrial1,4
1The Kinghorn Cancer Centre, Garvan Institute of Medical Research, Sydney, New South Wales, Australia.
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.
Insights
Targeting the cyclin-dependent kinase 4 (CDK4) pathway with palbociclib shows promise for pancreatic ductal adenocarcinoma (PDA). This CDK4 inhibition, guided by RB protein biomarkers, offers a personalized therapy approach for PDA subtypes.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Therapeutics
Background:
- Pancreatic ductal adenocarcinoma (PDA) exhibits significant molecular heterogeneity, limited effective treatments, and high mortality rates.
- The cyclin-dependent kinase 4 (CDK4) pathway, a key regulator of cell proliferation, is frequently deregulated in PDA.
- Developing tailored therapies for PDA is crucial due to its aggressive nature and poor prognosis.
Purpose of the Study:
- To develop a personalized treatment strategy for PDA by targeting the CDK4 pathway.
- To identify biomarkers predictive of response to CDK4/6 inhibition in PDA.
- To evaluate the efficacy of CDK4 inhibition in preclinical PDA models.
Main Methods:
- Correlated sensitivity to the CDK4/6 inhibitor palbociclib (PD-0332991) with proteomic and genomic data in 19 patient-derived PDA lines.
- Assessed in vivo efficacy of palbociclib monotherapy and combination treatments in various PDA tumor models.
- Investigated the mechanistic effects of therapy on tumor cell and extracellular matrix (ECM) signaling.
- Evaluated the prognostic relevance of the retinoblastoma (RB) protein biomarker in independent PDA patient cohorts.
Main Results:
- Subtype-specific efficacy of palbociclib-based therapy was observed across different stages of PDA progression, including primary, recurrent, and metastatic settings.
- Palbociclib disrupted the tumor extracellular matrix, leading to increased quiescence, apoptosis, enhanced chemosensitivity, and reduced invasion and metastasis.
- Retinoblastoma (RB) protein was identified as a potential predictive biomarker, prevalent in both operable and metastatic PDA.
Conclusions:
- CDK4 inhibition represents a promising therapeutic strategy for PDA, particularly when applied in a molecular subtype-specific manner.
- RB protein serves as a valuable biomarker for guiding CDK4-targeted therapy in PDA.
- This approach holds potential for improving outcomes in PDA patients compared to standard therapies.
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