On February 21, 2022 Published in Cancer Research Communications (1), a journal of the American Association for Cancer Research (AACR) (Free AACR Whitepaper), findings reported by investigators of the Vall d’Hebron Institute of Oncology’s (VHIO) Models of Cancer Therapies Group (Vall d’Hebron Barcelona Hospital Campus), and VHIO-born spin-off Peptomyc S.L., show that MYC inhibition is anti-metastatic in breast cancer (Press release, Peptomyc, FEB 21, 2022, View Source [SID1234608354]).
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The deregulation of the pleiotropic and ubiquitous MYC oncoprotein is implicated in almost all human cancers, and while its role as a promoter of tumorigenesis is beyond doubt, its function in the process of metastasis remains controversial. Contrasting reports suggest both a pro-metastatic and anti-metastatic function of MYC have largely precluded research assessing MYC inhibitors in the metastatic setting.
Thanks to two decades of research pioneered by Laura Soucek and her team, as well as the dedicated work of other groups, MYC inhibition is gaining pace in entering the clinic. Historically considered as an undruggable target, MYC now officially occupies a top spot on the most-wanted list of targets in cancer therapy.
Having shown potent anti-tumor activity of the MYC inhibitor Omomyc in multiple cancer cell lines and mouse models, regardless of their tissue of origin or driver mutations, Laura’s group and her Peptomyc team are developing viable, non-toxic pharmacological options for MYC targeting in the clinic.
"Considering the results of our previous studies that have clearly demonstrated Omomyc’s efficacy in primary tumors, we hypothesized that targeting MYC could also be efficacious against metastatic breast cancer," said Laura Soucek, corresponding author of this present study, Co-Founder & Chief Executive Officer (CEO) of Peptomyc, and an ICREA Research Professor.
Ringing in MYC inhibition in the metastatic setting
Metastases are genetically unstable. Information from a patient’s primary tumor might not mirror the metastasis, and one metastasis may vary from another, thus hampering the benefits of targeted therapies. Based on their data indicating the efficacy of MYC inhibition independently of the mutational profile of the tumor, the investigators hypothesized that this approach could overcome th challenge.
They also sought to establish if MYC inhibition could revert MYC’s promotion of epithelial-mesenchymal transition (EMT) and dedifferentiation, two important hallmarks of cancer metastasis.
The promise of Omomyc as a potential anti-metastatic therapy in breast cancer
To evaluate Omomyc’s efficacy against breast cancer and metastasis, the researchers used a panel of breast cancer cell lines, representative of all molecular subtypes of the disease. Assessing the transgenically expressed Omomyc first, they observed therapeutic impact in these cell lines and in cell-derived in vivo xenograft models.
They then confirmed that the same therapeutic impact can be achieved pharmacologically using the purified Omomyc mini-protein which demonstrated efficacy in cell lines in vitro, as well as in vivo, in cell-derived and patient-derived xenograft (PDX) models.
Results of this present study (1) shed important light on the efficacy of MYC inhibition in the metastatic setting, with particular focus on triple-negative breast cancer (TNBC). The investigators demonstrate for the first time that MYC inhibition by Omomyc is effective against TNBC by displaying potent anti-metastatic activity in vivo.
"Our results illuminate the relevance of MYC inhibition in metastatic disease, and are particularly timely now that MYC inhibitors, including our first Omomyc-derived compound, OMO-103, are reaching the clinic," added Laura Soucek.
Notably, OMO-103 entered clinical trials in May 2021, and is being tested in patients with various solid tumors in the Phase I/IIa MYCure study (2).
"We have now demonstrated that MYC inhibition by Omomyc exerts a dramatic effect on the metastatic process, from tumor growth, invasion to seeding. Findings evidenced a striking reduction in both primary tumor and metastatic growth. In some cases, metastases were even eradicated," said Daniel Massó-Vallés, first author of this study and a Postdoctoral Researcher and Project Manager at Peptomyc.
This study shows the promise of Omomyc as an anti-metastatic therapy against breast cancer and also challenges the controversial notion that MYC inhibition potentiates, rather than inhibits, tumor cell invasion and metastasis.
Results support the inclusion of metastatic TNBC patients in the ongoing MYCure trial, uphold MYC’s essential role in all aspects of tumorigenesis, and could ultimately lead to improved survival in this patient population.
This research was carried out in collaboration with investigators from other VHIO groups including Violeta Serra (PI, Experimental Therapeutics Group), and Joaquín Arribas (PI, Growth Factors Group), and researchers at CIEMAT (Madrid, Spain), and the Karolinska Institutet (Stockholm, Sweden).
This project was mainly funded by grants received from the Agència de Gestió d’Ajuts Universitaris i de Recerca (Agency for Management of University and Research Grants), Spanish Ministry of Science and Innovation, Spanish Ministry of Science and Technology – Institute of Health Carlos III, European Research Council (ERC), and the FERO Foundation.
References:
Daniel Massó-Vallés, Marie-Eve Beaulieu, Toni Jauset, Fabio Giuntini, Mariano F. Zacarías-Fluck, Laia Foradada, Sandra Martínez-Martín, Erika Serrano, Génesis Martín- Fernández, Sílvia Casacuberta-Serra, Virginia Castillo Cano, Jastrinjan Kaur, Sergio López- Estévez, Miguel Ángel Morcillo, Mohammad Alzrigat, Loay Mahmoud, Antonio Luque-García, Marta Escorihuela, Marta Guzman, Joaquín Arribas, Violeta Serra, Lars-Gunnar Larsson, Jonathan R. Whitfield & Laura Soucek. MYC inhibition halts metastatic breast cancer progression by blocking growth, invasion and seeding. Cancer Res Commun. 2022;2:110–30. doi: 10.1158/2767-9764.CRC-21-0103.
Phase 1/2 Study to Evaluate Safety, PK and Efficacy of the MYC-Inhibitor OMO-103 in Solid Tumours (MYCure). ClinicalTrials.gov Identifier: NCT04808362.