RBM45

SOUTH SAN FRANCISCO, Calif.--(BUSINESS WIRE)-- #BreastCancer --Circle Pharma, a clinical-stage biopharmaceutical company dedicated to discovering and developing a new generation of macrocycle therapies, today announced that preclinical data from its lead candidate, CID-078, a first-in-class oral macrocycle cyclin A/B RxL inhibitor, has been selected for a late-breaking poster presentation at the 36th EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics, also known as the Triple Meeting. The symposium is taking place from October 23-25, 2024, in Barcelona, Spain. Poster presentation details are below: Author: Wang et al. Title: CID-078, a First-in-Class Oral Macrocycle Cyclin A/B RxL Inhibitor, Demonstrates Anti-Tumor Activity in ESF-driven Cancers Abstract Number: PB-515 Session Title: Late breaking posters Date and Time: October 23, 2024 (6 a.m. EST/12 p.m. CEST) to October 25, 2024 (11 a.m. EST/5 p.m. CEST) The digital poster can be viewed here. The pre-clinical data shows CID-078 demonstrated single-agent tumor activity across tumor cell line and in vivo models with dysregulated cell cycle (CDK-RB-E2F) function. Notably, tumor regressions were observed in small-cell lung cancer (SCLC), non-small-cell lung cancer (NSCLC), and triple-negative breast cancer (TNBC) preclinical models. Within specific indications, CID-078 single agent activity was correlated with RB1 mutation, high E2F target, or G2M checkpoint hallmark pathway scores. The cumulative pre-clinical data suggests that CID-078 holds promise as a monotherapy for patients with these cancers. A multi-center phase 1 clinical trial (NCT06577987) is currently enrolling patients. About CID-078 CID-078 is an orally bioavailable macrocycle with dual cyclin A and B RxL inhibitory activity that selectively targets tumor cells with oncogenic alterations that cause cell cycle dysregulation. In biochemical and cellular studies, Circle Pharma’s cyclin A/B RxL inhibitors have been shown to potently and selectively disrupt the protein-to-protein interaction between cyclins A and B and their key substrates and modulators, including E2F (a substrate of cyclin A) and Myt1 (a modulator of cyclin B). Preclinical studies have demonstrated the ability of these cyclin A/B RxL inhibitors to cause single-agent tumor regressions in multiple in vivo models. A multi-center phase 1 clinical trial ( NCT06577987 ) is currently enrolling patients. About Circle Pharma, Inc. South San Francisco-based Circle Pharma is advancing the discovery and development of intrinsically cell-permeable macrocycles that can be delivered by multiple routes, including oral administration. Circle Pharma’s MXMO™ platform combines structure-based rational drug design and advanced synthetic chemistry to develop a new generation of macrocycle therapies for challenging targets to address unmet clinical needs. Circle Pharma is focusing its development efforts on cyclins, which are master regulators of the machinery that controls the progression of cells through the cell cycle and are key drivers in many cancers. To learn more about Circle Pharma, please visit . Contacts Media Contact: Roslyn Patterson 650.825.4099 roslyn.patterson@circlepharma.com

SAN FRANCISCO, March 25, 2024 (GLOBE NEWSWIRE) -- ProLynx Inc. announced that the first patient was included in TOPOLOGY by investigator Dr. Delphine Loirat, with a Phase II clinical trial investigating PLX038 (PEG~SN-38) for locally-advanced or metastatic triple-negative breast cancer (TNBC). Patients will have been previously treated with at least two therapies, including the antibody-drug conjugate (ADC) sacituzumab govitecan (SG; Trodelvy). The TOPOLOGY trial is run by Institut Curie (Paris and Saint Cloud, France), with principal investigator Prof. Francois-Clement Bidard . PLX038 is a long-acting prodrug of the topoisomerase 1 (Top1) inhibitor, SN-38, which is also the active component of anti-cancer agents irinotecan and the ADC SC. Top1 inhibitors cause DNA breaks and kill tumors that are unable to repair the damage. Previously, Curie researchers showed that about one-third of TNBC patients have defects in DNA damage repair, and should respond to an effective SN-38-based therapy (Coussy et al., 2020). In PLX038, SN-38 is covalently bound to a circulating nanoparticle and is slowly released to provide free SN-38 with a long half-life, low Cmax, and high exposure – important facets for optimal safety and efficacy. Importantly, in preclinical studies PLX038 was shown to accumulate and be retained in solid tumors, where it slowly releases its SN-38. SG is an anti-TROP2 ADC with an SN-38 payload that was recently approved for use in advanced TNBC. However, the rapid spontaneous linker hydrolysis in SG releases a large amount of SN-38 cargo systemically, which may in part contribute to its efficacy and also in part be responsible for systemic side effects. Unfortunately, the median progression-free survival after SG therapy is only ~6 months due to resistance, and there are limited rescue therapies available. ProLynx co-founder and President Daniel V. Santi commented, “Although the active SN-38 payload of PLX038 and SG is the same, the anti-tumor mechanisms of the prodrugs are quite different; and, some mechanisms of resistance may also quite be different (Santi et al., Biodrugs,2024). Taken together, it is reasonable to believe that PLX038 may be effective in SG-resistant tumors.” Curie investigator Francois-Clement Bidard added, “As with our earlier preclinical study of the correlation of efficacy of irinotecan with BRCAness and SFLN11 biomarkers, TOPOLOGY will assess association of PLX038 efficacy with homologous recombination defects, and biomarkers such as SFLN11 expression and RB1 loss. If confirmed in TOPOLOGY, these biomarkers will allow pre-selection of patients most likely to respond to the drug.” ProLynx is a San Francisco biotechnology company developing proprietary systems to improve the pharmacokinetics and efficacy of important therapies ( ). Institut Curie, France’s leading cancer center, combines a renowned research center and hospital which treats all types of cancer. Institut Curie has 3 sites (Paris, Saint-Cloud and Orsay) with over 3,700 health professionals working on treatment, research and teaching ( ) Information on this clinical trial is available at clinicaltrials.gov, NCT06162351. Contact BD@ProLyninc.com

While Daiichi Sankyo's DS-7300a has been shown to be effective in interim human data from early trials on the drug in castration-resistant prostate cancer, there’s reason to think that it might not work as well on its own in some subtypes. New preclinical research on Daiichi Sankyo’s antibody-drug conjugate DS-7300a suggests it might be more effective against hard-to-treat forms of prostate cancer when used alongside a long-standing chemotherapy drug. According to the results of a study published Nov. 15 in Science Translational Medicine, experiments assessing DS-7300a with and without the blood cancer chemo agent decitabine found that the combo was more effective in mice with neuroendocrine prostate cancer (NEPC) and a form where the tumor suppressor gene RB1 is mutated or lost. The research was sponsored in part by the Japanese pharma and performed by scientists at the Dana-Farber Cancer Institute. In general, prostate cancer is one of the most treatable if detected early. But some advanced types require castration, where hormones or surgery are used to lower testosterone levels and stop the cancer from growing. About 10% to 20% are resistant to treatment with castration—and, of these, a relatively high number have either changes to RB1 or have evolved into NEPC, both of which make them especially tough to treat. “RB1 genomic loss is uncommon at prostate cancer diagnosis but RB1 deletion or mutation is present in approximately 10 to 20% of castration-resistant prostate cancers,” lead author Himisha Beltran, M.D., a genitourinary oncologist and director of translational research within medical oncology at Dana-Farber, explained to Fierce Biotech Research via email. NEPC makes up another 15 to 20%, she added. Both scenarios make the prognosis far more dire. Beltran’s team had previously identified changes in DNA that distinguish NEPC from other forms of prostate cancer, including some that resulted in higher production of enzymes called DNA methyltransferases. Now, they wanted to find out how these DNA changes—also known as DNA methylation—made prostate cancer harder to treat and whether the most highly expressed DNA methyltransferases, DNMT1 and DNMT3A, might be a viable drug target. For that, they turned to decitabine, a chemotherapy drug that has been used for myelodysplastic cancers since the 1980s. Its anti-cancer activity stems from its ability to inhibit DNA methyltransferases, including DNMT1 and DNMT3A. Studies on NEPC patient-derived cell lines and organoids showed the drug could effectively kill cancer cells, findings that were validated in mouse models of the disease. They also saw differences in DNA markers between treated and untreated mouse models that indicated the drug was effectively preventing DNA methylation. These findings led the researchers to wonder whether the benefit from using decitabine to inhibit DNMT1 and DNMT3a could extend beyond NEPC to remedy other types of DNA changes found in advanced prostate cancer. They homed in on RB1, the deletion or mutation of which makes the disease more resistant to treatment as well as more likely to evolve into NEPC. Cell studies and experiments with a mouse model of prostate cancer without the RB1 gene showed that the drug was effective in inhibiting tumor progression, though it didn’t have an effect on cancer in models where the gene was intact. Additional analysis showed that, like in the case of NEPC, it worked by inhibiting the DNMTs. Knowing that DNMT inhibition could lead to the expression of other cancer cell genes, the researchers next focused on seeing whether any of them might make good targets for a combination treatment with decitabine. RNA and DNA sequencing analysis gave them 245 potential candidates, one of which stood out as having some ideal characteristics: the gene for a receptor called B7-H3, the target of prostate tumor treatments under investigation including DS-7300a. While DS-7300a has been shown to be effective in interim human data (PDF) from early trials on the drug in castration-resistant prostate cancer, there’s reason to think that it might not work as well in NEPC or RB1-mutated tumors. That’s because those forms have lower expression of B7-H3 than other types, research shows, which could make them less vulnerable to the drug. Beltran’s lab reasoned that treating NEPC and RB1-mutated tumors with decitabine might make them more susceptible to DS-7300a by raising levels of B7-H3. After showing through cell studies that the combination of decitabine and DS-7300a was indeed synergistic—and that DS-7300a alone wasn’t as effective against cancer cells where B7-H3 expression was low—the researchers tested it out in mouse models. Just as they saw in vitro, DS-7300a had anti-tumor effects in mice with both high- and low-B7-H3-expressing tumors but was more effective against tumors with low levels of B7-H3 when combined with decitabine. The study comes with caveats. It only looked at a limited number of prostate cancer models, the researchers wrote in their report, so it couldn’t assess all the possible relationships between DNA methylation, gene expression and treatment response according to a prostate cancer’s specific genotype and phenotype. On top of that, it’s not clear what level of B7-H3 should be expressed by tumors for them to respond to therapy, Beltran noted. “This can be investigated further in ongoing trials,” she said. Beltran’s team plans to study whether NEPC and prostate cancers with the loss of RB1 respond to monotherapy with decitabine in clinical trials. They also hope to launch a study on the drug in combination with DS-7300a, the effectiveness of which will be assessed in part according to certain biomarkers, she said.