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
2459 - Does bevacizumab increase joint pain ? Preliminary results of BEVARTHRALGIA Study
Presenter: Vauleon Enora
Session: Poster Display session 1
Resources:
Abstract
4913 - Prostatic cancer androgen deprivation therapy and bone health in carcinoma prostate.
Presenter: Gouri Shankar Bhattacharyya
Session: Poster Display session 1
Resources:
Abstract
1352 - Patterns of care for patients with metastatic bone disease in solid tumors – a cross-sectional study (SAKK 95/16)
Presenter: Michael Mark
Session: Poster Display session 1
Resources:
Abstract
6002 - Infection-Related Mortality in Different Types of Cancers
Presenter: Mohamed Gouda
Session: Poster Display session 1
Resources:
Abstract
5643 - Survival Trends in Critically ill Oncology Patients: impact of patient’s eligibility to post-ICU chemotherapy
Presenter: Edith Borcoman
Session: Poster Display session 1
Resources:
Abstract
3097 - Development and validation of a multivariable prediction model for 6-month mortality in older cancer patients: the GeriAtrIc-Tumor Score of PrEdiction for Early Death (GAIT SPEED)
Presenter: Angeli Angeli
Session: Poster Display session 1
Resources:
Abstract
856 - A Longitudinal Tracking and Quantitative Assessment of Paclitaxel-Induced Peripheral Neurotoxicity
Presenter: Ayumu Matsuoka
Session: Poster Display session 1
Resources:
Abstract
1662 - Efficiency of controlled cryotherapy in prevention of chemotherapy induced peripheral neuropathy (CIPN)
Presenter: Trudi Schaper
Session: Poster Display session 1
Resources:
Abstract
2766 - The Validity of Evaluations for Chemotherapy-Induced Peripheral Neuropathy (CIPN)
Presenter: Teppei Yamada
Session: Poster Display session 1
Resources:
Abstract
5683 - Prevention of chemoradiation-related mucositis in patients with head and neck cancer using dexamethasone-based mouthwash: A phase II randomized double-blind, placebo-controlled study
Presenter: Naiyarat Prasongsook
Session: Poster Display session 1
Resources:
Abstract