Findings from a preclinical study led by VHIO’s Models of Cancer Therapies Group directed by Laura Soucek, an ICREA Research Professor and co-Founder and CSO of the VHIO and ICREA spin-off company Peptomyc S.L, demonstrate that Omomyc—the only direct MYC inhibitor to have successfully completed a phase I clinical trial—causes DNA damage in cancer cells which is synergistically enhanced in combination with poly (ADP-ribose) polymerase inhibitors (PARPi).

Published in Cell Reports, these findings could potentially offer a new therapeutic opportunity to overcome PARPi resistance in this patient population.

Development of a disruptive MYC inhibitor

Under normal conditions, MYC is a transcription factor that plays a critical role in regulating the activation of genes related to cell division in an orderly manner.

The deregulation of the MYC gene, occurring in up to 70% of human cancers, drives the transcription of genes implicated in the uncontrolled growth of tumour cells and the development of metastasis and disease recurrence, making it one of the most sought-after targets in oncology.

Directed by Laura Soucek, over two decades of research aimed at combating resistance to therapy and promoting cancer regression through MYC inhibition led to the in-house development of the Omomyc therapeutic mini-protein (a.k.a.OMO-103), brought to clinical trials by Peptomyc, which Soucek co-founded in 2014.

Having previously demonstrated a manageable safety profile and promising anti-tumour activity in all-comers solid tumour patients, this first Omomyc-derived compound is currently being tested in a phase Ib in patients with metastatic pancreatic cancer, and in a phase II clinical trial in patients with advanced osteosarcoma.

MYC’s dual role in DNA damage response and repair

“The oncogenic capabilities of MYC have been well known for decades. More controversial, however, is its role in DNA damage and repair, where MYC has a dual role. On the one hand, it promotes genomic instability through replication stress, and on the other hand, it enhances certain DNA repair mechanisms. These opposing functions create a delicate balance that enables cancer cells to maintain elevated levels of genomic stress without compromising survival,” said Fabio Giuntini, a Postdoctoral Researcher of VHIO’s Models of Cancer Therapies Group and first author of this present study.

Synergistic effect of Omomyc-PARPi in combination

Triple-negative breast cancer (TNBC) accounts for approximately 15-20% of all breast cancer diagnoses and is a particularly aggressive tumour type in which MYC is highly dysregulated, and for which there are few therapeutic options.

One of these available treatments are PARPi which target tumours with germline mutations in the BRCA1/2 genes (representing about 10-15% of TNBC).

Among these patients, many only respond to PARPi for a limited period due to the emergence of cancer drug resistance.

As reported in this present study, the investigators used PARPi-resistant cell lines, cell-derived and patient-derived xenograft models (CDXs and PDXs) to characterise the mechanism of action of Omomyc in TNBC and found a clear decrease in the expression of DNA damage repair (DDR)-related genes with Omomyc monotherapy.

In parallel, they observed that Omomyc induced more DNA damage.

“This observation encouraged us to combine Omomyc and PARPi, revealing a powerful cooperative effect both in vitro and in vivo, resulting in anti-tumour response, increased DNA damage and apoptosis. Strikingly, the combination in vivo in cell line-derived and patient-derived xenografts created a synergistic therapeutic effect, achieving a superior disease control rate than with either monotherapy alone,” said Laura Soucek, corresponding author of this work.

Notably, PARPi-resistant PDXs showed a significantly higher MYC transcriptional activity compared to sensitive ones, and their resistance was overcome by treatment with Omomyc.

Finally, in samples from patients with TNBC obtained pre-treatment with PARPi, the transcriptomic signature of MYC enabled the researchers to predict response to treatment, suggesting that this biomarker could help identify patients who are more likely to benefit from this type of therapy.

“Our results unveil the role of MYC as a driver of  PARPi resistance, and we propose Omomyc as a novel DNA-damaging agent, capable of cooperating with PARPi and resensitising PARPi-resistant triple-negative breast cancer to this type of targeted therapy,” concluded Soucek.

Source: Vall d'Hebron Institute of Oncology