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Read original article at Business Wire
Circle Pharma, in collaboration with the laboratory of Violeta Serra, Ph.D., at Vall d’Hebron Institute of Oncology (VHIO) in Barcelona, Spain, recently unveiled preclinical data demonstrating the efficacy of Circle’s oral Cyclin A/B inhibitor macrocycles in patient-derived breast cancer tumor models. This significant development was presented at the 2023 AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics
The study in 40 breast cancer cell lines identified an association between hallmark pathway scores in E2F, G2/M, and mitotic spindle pathways and sensitivity to Cyclin A/B inhibition. Most notably, multiple triple-negative breast cancer (TNBC) cell lines and luminal B breast cancer cell lines displayed sensitivity to Cyclin A/B inhibition. These findings were instrumental in selecting TNBC and luminal breast cancer patient-derived tumor models for subsequent in vivo efficacy studies. In these in vivo studies, oral administration of Circle’s Cyclin A/B inhibitor led to substantial tumor regression in both TNBC and luminal breast cancer models, with complete response observed in a luminal B breast cancer model derived from a patient whose tumor had previously progressed following multiple treatments, including with a CDK4/6 inhibitor.
Breast cancer is the second leading cause of cancer-related deaths in women globally. Triple negative breast cancer, which accounts for 10-20% of all breast cancer cases, is an aggressive and challenging subtype of breast cancer, associated with poor prognosis and high risk of relapse1. Because TNBC lacks specific receptors (estrogen, progesterone, or HER2) that some other breast cancers have, many newer therapies used to target these receptors in other forms of breast cancer are not effective. Luminal breast cancers are hormone receptor-positive and generally less aggressive than TNBC. Luminal breast cancers can be further divided into two subtypes: luminal A (HR+/ER+/HER2+) and luminal B (HR+/PR+/HER2-). These two subtypes make up about 70% of all breast cancer cases2.
1 American Society of Clinical Oncology. (2017 May) Triple-Negative Breast Cancer: Current Practice and Future Directions. Ricardo L.B. Costa and William J. Gradishar.
2 Nature. (2000; 406) Molecular portraits of human breast tumours. Perou CM, Sorlie T, Eisen MB, et al.
Read original article at Business Wire
SAN FRANCISCO, Calif.–(BUSINESS WIRE)–Circle Pharma announced today that two poster presentations at the American Association for Cancer Research (AACR) Annual Meeting held April 14-19, in Orlando, Florida, highlight promising pre-clinical data of its first-in-class orally bioavailable macrocyclic cyclin A/B inhibitors targeting intractable cancers. Circle expects to advance its cyclin A/B inhibitor program into IND-enabling studies later this year and subsequently into clinical development for testing in a range of cancer types, including SCLC.
The data presented by Circle Pharma shows activity across a wide range of human tumor cell lines and tumor regression in xenograft models of small cell lung carcinoma (SCLC) and ovarian cancer. Pre-clinical development of orally bioavailable macrocycles with dual cyclin A and B inhibitory activity drive synthetic lethality in multiple tumor types. The compounds are shown to be well-tolerated in mice with no observed body weight loss, neutropenia, or depletion of bone marrow across all dose regimens. In vitro studies showed that target engagement in cells leads to displacement of E2F1 from Cyclin A:CDK2 and Myt1 from Cyclin B:CDK1, and the compounds induce DNA damage, G2/M arrest, and apoptosis. The presentation further showed that sensitivity in SCLC cell lines is correlated with RB dysfunction and E2F1 target gene expression.
In addition, studies conducted by the laboratory of Matthew Oser at Dana Farber Cancer Institute (DFCI) validate that cyclin A/B inhibitors induce mitotic arrest and apoptosis in SCLC cell lines. The researchers deployed a genome wide CRISPR/Cas9 positive selection screen to identify that activation of the mitotic spindle assembly checkpoint (SAC) complex by the kinase MSP1 is a dominant mechanism for selective cancer cell killing by the cyclin A/B inhibitors. Dr. Oser’s laboratory at DFCI was sponsored by Circle Pharma.
| Program | Presentation Details |
|---|---|
| Cyclin A/B | Abstract Number: 1559 Abstract Title: Mechanisms responsible for hypersensitivity of small cell lung cancers to novel cyclin A/B RxL macrocyclic peptide inhibitors Session Title: Experimental and Molecular Therapeutics Session Type: Poster |
| Cyclin A/B | Abstract Number: 1560 Abstract Title: Orally bioavailable macrocycles that target cyclins A and B RxL motifs cause tumor regression in xenograft models and in vitro show activity across multiple cancer types Session Title: Experimental and Molecular Therapeutics Session Type: Poster |
About Circle Pharma, Inc.
Circle is a biopharmaceutical company advancing the discovery and development of intrinsically cell-permeable macrocycles that can be delivered by multiple routes, including oral administration. Circle’s MXMO™ platform combines structure-based rational drug design and advanced synthetic chemistry to develop first-in-class macrocycle therapeutics for challenging targets to address unmet clinical needs. Circle’s macrocycle can address both intra- and extra-cellular therapeutic targets and is applicable across a wide range of serious diseases; the company is initially focusing its development efforts on intracellular protein-protein interactions that are key drivers in cancer but have remained elusive to other treatment modalities. Circle is headquartered in South San Francisco and has raised $160 million to date from leading life sciences investors including The Column Group, Nextech, Pfizer and Eli Lilly.
To learn more about Circle Pharma please visit www.circlepharma.com.
Contacts
Circle Pharma Media Contact:
Eleanor Lim
650.825.4099
info@circlepharma.com
Read original article at Business Wire
The Company’s presentation provided details of its progress towards structure-guided macrocycles that inhibit the protein-protein interaction between the cyclin A:CDK2 complex and key substrates that are phosphorylated by this complex. Inhibition of Cyclin A substrate binding has been postulated to be synthetic lethal in Rb mutated cancers. The data presented included evidence that macrocycle inhibitors of cyclin A induce G2/M arrest and apoptosis in small cell lung cancer (SCLC) cell lines and have anti-tumor efficacy in SCLC xenograft animal models. Circle plans to advance its cyclin A inhibitor program to the clinic for testing in a range of cancer types, including SCLC where Rb mutations are highly prevalent.
The presentation was made as part of the Mechanisms of Drug Action / Experimental and Molecular Therapeutics session at the AACR meeting, Abstract No. 5379.
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