Abstract 5236
Background
Poly-ADP-Ribose Polymerase inhibitors (PARPi) constitute a class of drugs that interfere with DNA damage response and are already available or in current advanced development either alone or in combination with DNA damaging agents such as chemotherapeutics. Some features of colorectal cancer (CRC), like microsatellite instability and MAPK-induced replication stress, make it a good candidate for exploring the combination of PARPi with chemotherapeutics. Previous data have evidenced how PARPi/chemotherapy combinations are effective in various cancers, albeit early clinical trials showed only modest activity in unselected CRC patients.
Methods
We tested the activity of the PARPi niraparib (MK-4827) used alone or in combination with either 5-fluorouracil, oxaliplatin or irinotecan (SN38) in a panel of 12 CRC cell lines with known molecular characteristics. Proliferation, cell cycle and apoptosis assays were performed. A correlation between combination synergism and the following molecular features was obtained: RAS/BRAF mutation, HER2 amplification, microsatellite status, mutational and transcriptomic profiles from the Cancer Cell Line Encyclopedia (CCLE) database. Mice xenografts using the most representative cell lines are ongoing. Patient-derived 3D primary cultures (PDPCs) are being used to confirm the data obtained in vitro.
Results
Niraparib is synergistic with the investigated chemotherapeutics in most of the cell lines explored. The best candidate for combination is SN38, which is synergistic in 9/12 cell lines analysed. MAPK activation, microsatellite instability (MSI) and mutations in genes involved in homologous recombination repair (HRR) are good predictors of synergism. Transcriptomic analysis is ongoing. Mice xenografts and PDPCs models are in progress and will be presented at the Congress.
Conclusions
The combination of niraparib and irinotecan/SN38 is effective in an in vitro model of CRC. MAPK activation, MSI and mutation in HRR-associated genes are predictors of synergism and are currently being validated in in vivo and ex vivo models. These findings could lead to a better patient selection for this combination in CRC.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
The authors.
Funding
Università della Campania Luigi Vanvitelli; Associazione Italiana per la Ricerca sul Cancro (AIRC).
Disclosure
P.P. Vitiello: Research grant/Funding (institution), Travel/Accommodation/Expenses: Amgen; Research grant/Funding (institution): Bayer; Research grant/Funding (institution): Ipsen; Research grant/Funding (institution): Merck; Research grant/Funding (institution): Roche; Travel/Accommodation/Expenses: BMS; Travel/Accommodation/Expenses: Sanofi-Genzyme. D. Ciardiello: Travel/Accommodation/Expenses: Sanofi. C. Cardone: Research grant/Funding (institution): Ipsen; Research grant/Funding (institution): Roche; Research grant/Funding (institution): Merck; Research grant/Funding (institution): Amgen; Research grant/Funding (institution): Bayer. G. Martini: Research grant/Funding (self): Amgen. C. Borrelli: Travel/Accommodation/Expenses: BMS. L. Poliero: Travel/Accommodation/Expenses: BMS. V. De Falco: Travel/Accommodation/Expenses: BMS; Travel/Accommodation/Expenses: Novartis. E.F. Giunta: Travel/Accommodation/Expenses: Novartis; Travel/Accommodation/Expenses: BMS. M. Terminiello: Travel/Accommodation/Expenses: BMS. T. Troiani: Research grant/Funding (institution): Roche; Research grant/Funding (institution): Merck; Research grant/Funding (institution): Bayer; Travel/Accommodation/Expenses: Servier; Travel/Accommodation/Expenses: Amgen; Travel/Accommodation/Expenses: Sanofi; Travel/Accommodation/Expenses: Novartis. F. Ciardiello: Advisory/Consultancy, Research grant/Funding (institution): Merck; Advisory/Consultancy, Research grant/Funding (institution): Bayer; Advisory/Consultancy, Research grant/Funding (institution): Amgen; Advisory/Consultancy, Research grant/Funding (institution): Roche; Advisory/Consultancy: Servier; Advisory/Consultancy: Pfizer; Research grant/Funding (institution): Ipsen. E. Martinelli: Honoraria (self), Research grant/Funding (institution): Amgen; Honoraria (self), Research grant/Funding (institution): Bayer; Honoraria (self), Research grant/Funding (institution): Merck; Research grant/Funding (institution): Roche; Honoraria (self), Research grant/Funding (institution): Servier. All other authors have declared no conflicts of interest.
Resources from the same session
603 - Mendelian Randomization Study of Alzheimer's Disease and Lung Cancer
Presenter: Huaqiang Zhou
Session: Poster Display session 1
Resources:
Abstract
4462 - Spanish registry of thoracic tumors (TTR): Interim analyses of comorbidities, risk associations, personal and family history of cancer
Presenter: Rafael Lopez Castro
Session: Poster Display session 1
Resources:
Abstract
3957 - Pleural effusion TGF-beta is highly diagnostic and prognostic in malignant pleural mesothelioma
Presenter: Paul Stockhammer
Session: Poster Display session 1
Resources:
Abstract
3583 - Immune microenvironment modulation by p14/ARF in Malignant Pleural Mesothelioma
Presenter: Giulia Pasello
Session: Poster Display session 1
Resources:
Abstract
4255 - Tumor Treating Fields plus chemotherapy for first-line malignant pleural mesothelioma (MPM): radiological responses in the STELLAR trial
Presenter: Federica Grosso
Session: Poster Display session 1
Resources:
Abstract
1803 - Effects of Tumor Treating Fields (TTFields; 150 kHz) and Cisplatin or Pemetrexed Combination Therapy on Mesothelioma cells In Vitro and In Vivo
Presenter: Mijal Munster
Session: Poster Display session 1
Resources:
Abstract
2660 - Real world use of systemic therapy in elderly patients with malignant pleural mesothelioma (MPM)
Presenter: Susana Cedres
Session: Poster Display session 1
Resources:
Abstract
3150 - Pemetrexed/Cisplatin versus Gemcitabine/Cisplatin as first-line treatment for Egyptian patients with malignant pleural mesothelioma
Presenter: Mohamed Alorabi
Session: Poster Display session 1
Resources:
Abstract
4319 - Accuracy of pathologic evaluation for thymic epithelial tumors in an Italian reference Centre
Presenter: Giulia Galli
Session: Poster Display session 1
Resources:
Abstract
4811 - Comprehensive genomic profiling of thymic carcinoma in a sample Chinese population
Presenter: Baohui Han
Session: Poster Display session 1
Resources:
Abstract