Abstract 4290
Background
The phosphatidylinositol 3-kinase (PI3K) pathway plays a central role in cell proliferation and survival in human cancer. Mutations in PIK3CA, the gene coding the p110α catalytic subunit of PI3K, are frequent in cancer and result in PI3K pathway activation. About 25% of HER2-positive breast cancers also carry PIK3CA mutations, known to confer resistance to anti-HER2 therapy. Here we report the preclinical characterization of MEN1611, a potent and selective orally available PI3K inhibitor, showing high activity against p110α mutant isoforms and sparing the δ isoform.
Methods
In vivo efficacy studies were evaluated through Tumour Volume Inhibition % (TVI%) and mRECIST criteria using cancer cell lines and patient-derived xenograft (PDX) models. Pathway activation and protein degradation analyses were performed by western blot and capillary electrophoresis immunoassay. Immune modulation was evaluated using murine macrophages differentiated in vitro.
Results
Consistent with its mechanism of action, MEN1611 down-modulates the PI3K/AKT signaling as well as selected downstream targets, both in vitro and in vivo. MEN1611 acts synergistically when combined with trastuzumab in several HER2-positive PIK3CA-mutated breast cancer cell lines and patient-derived xenograft models. The in vivo efficacy in trastuzumab-resistant models is supported by a long-lasting antitumor activity, paralleled by mechanistic down-regulation of pharmacodynamic biomarkers. Moreover, MEN1611 showed the ability to induce a dose-dependent alpha-isoform depletion, and to modulate the macrophage polarization towards a pro-inflammatory phenotype, consistent with its capability to co-inhibit P110γ.
Conclusions
Overall, these preclinical data support the progression in the development of MEN1611 in breast cancer and pave the way to the B-Precise-01 clinical study, a multicentre phase Ib study.
Clinical trial identification
NCT03767335.
Editorial acknowledgement
Legal entity responsible for the study
Menarini Ricerche S.p.A.
Funding
Menarini Ricerche S.p.A.
Disclosure
A. Fiascarelli: Full / Part-time employment: Menarini RIcerche S.p.A. G. Merlino: Full / Part-time employment: Menarini Ricerche S.p.A. S. Capano: Full / Part-time employment: Menarini Ricerche S.p.A. A. Paoli: Full / Part-time employment: Menarini Ricerche S.p.A.. A. Bressan: Full / Part-time employment: Menarini Ricerche. M. Bigioni: Full / Part-time employment: Menarini Ricerche S.p.A.. M. Scaltriti: Advisory / Consultancy: Memorial Sloan-Kettering Cancer Center. J. Arribas: Advisory / Consultancy: Vall d’Hebron Institute of Oncology. C. Bernadó Morales: Advisory / Consultancy: Vall d’Hebron Institute of Oncology. A. Pellacani: Leadership role, Full / Part-time employment: Menarini Ricerche S.p.A.. M. Salerno: Leadership role, Full / Part-time employment: Menarini Ricerche. M. Binaschi: Leadership role, Full / Part-time employment: Menarini Ricerche S.p.A.
Resources from the same session
5520 - Patient’s Usability Test results of a CINV Diary Application For Smartphones
Presenter: Paz Fernandez
Session: Poster Display session 3
Resources:
Abstract
2323 - Colorectal Telephone Assessment Pathway (CTAP) - A viable means of shortening time to a definitive diagnosis of Colorectal Cancer (CRC)
Presenter: Harriet Watson
Session: Poster Display session 3
Resources:
Abstract
6119 - Cancer Nursing and Social Media: Capturing the Zeitgeist
Presenter: Mark Foulkes
Session: Poster Display session 3
Resources:
Abstract
1776 - Examination of mobile applications on breast cancer
Presenter: AYDANUR AYDIN
Session: Poster Display session 3
Resources:
Abstract
4128 - E-health effectiveness to increase patient adherence for immunotherapy; a cost-benefit study.
Presenter: Maria José Dias
Session: Poster Display session 3
Resources:
Abstract
3219 - Experiences of internet-based stepped care among individuals with recently diagnosed cancer and symptoms of anxiety and/or depression
Presenter: Anna Hauffman
Session: Poster Display session 3
Resources:
Abstract
5010 - What do cancer patients know about their immunotherapy treatment?
Presenter: Mónica Arellano
Session: Poster Display session 3
Resources:
Abstract
4503 - Prospective Comparison of Travel Burden, Cost and Time to Obtain Tumor Board Treatment Plan Through In-Person Visits vs. an AI Enabled Health Technology (N=1803)
Presenter: Rajendra Badwe
Session: Poster Display session 3
Resources:
Abstract
4123 - Cancer care through the fire and flames: 3-year experience in the utilisation of electronic consultation and referral system at the Red Zone in Southern Thailand
Presenter: Nanthiya Rattanakhot
Session: Poster Display session 3
Resources:
Abstract
2087 - The effect of e-mobile education on the quality of life in women with breast cancer
Presenter: Derya ÇInar
Session: Poster Display session 3
Resources:
Abstract