Temple Therapeutics Reveals Breakthrough Findings on Ovarian Cancer at AACR 2023
Temple Therapeutics, a biotechnology company pioneering a female-focused precision medicine approach, presented new in vitro and in vivo data on TTX335o, the first drug candidate from the company’s platform that won the Eurostar Eureka peer-reviewed grant process in 2019 for ovarian cancer, and the novel ovarian cell target, lemur tyrosine kinase 3 (LMTK3). The new data was provided at a poster presentation at the American Association of Cancer Research (AACR) Annual Meeting, which took place on April 14-19, 2023 in Orlando.
“While survival rates for ovarian cancer are creeping up to the 50% level, it is clear that the vast majority of women are diagnosed too late,” said Sanj Singh, CEO of Temple Therapeutics. “It has been referred to as the silent killer by some, and others have described it as the neglected or ignored killer. Despite its lethality as the most dangerous gynecological cancer, the field has been sparsely researched. We are changing that. As we recognize World Ovarian Cancer Day today, we can do better. Our sisters, aunts, spouses, friends, co-workers, mothers, and grandmothers are affected.”
TTX335o is based on the breakthrough discovery of LMTK3 and its mechanism of action. Increased levels of LMTK3 have been shown to affect the transcription of genes promoting DNA repair, cell viability, and tumorigenesis which activates cell death pathways specific to cancer cells without harming normal cells.
Preclinical data presented at AACR 2023 included:
- LMTK3 protein was detected in 98% of ovarian cancer tissues collected from 204 patients in various stages and major histology and localized in the nucleus of health cells and in the cytoplasm of tumor cells.
- Risk of death among ovarian cancer patients with more cytoplasmic than nuclear LMTK3 levels was particularly high during the first year after diagnosis. This suggests cytoplasmic LMTK3 expression correlates with poor survival which serves as a potential prognostic marker for ovarian cancer patient outcomes (p<.01).
- TTX335o specifically targets apoptosis, a major determinant in uncontrolled cell growth in ovarian cancer through a novel integrin (αV/β1), monomeric myeloperoxidase (mMPO), and LMTK3 signaling pathways. Knocking down LMTK3 also induced cell death in ovarian cancer, and more importantly, did not harm normal cells.
- In vitro and in vivo studies seem to validate LMTK3 as a specific target and predictor of clinical outcomes in ovarian cancer.
Both nuclear and cytoplasmic LMTK3 expressions correlated with tumor grade and patient survival in cancers such as breast and colorectal cancer. The clinical significance of the LMTK3 gene was tested from 204 early-stage (stage I-II) ovarian cancer patients of all major subtypes. Results from this study revealed a higher cytoplasmic to nuclear localization of LMTK3 correlated with worse overall survival (P<0.01). More importantly, engineered novel target-specific molecules, collectively known as TTX335o, significantly induced ovarian cancer cell death. Strikingly, TTX335o molecules are also effective in cells resistant to chemotherapy (e.g., docetaxel or cisplatin) as in sensitive cells.
“The discovery of this novel target almost five years ago was surprising and exciting because we thought, what if this could be an early detection biomarker,” said Dr. Ghassan Saed, Inventor and Lead Researcher and Associate Professor of Gynecology Oncology at Wayne State University and Karmanos Cancer Center in Michigan. “Dr. Helou at Sahlgrenska Cancer Center screened the target across 204 Stage I-II ovarian cancer patient samples and saw firsthand the correlation data of expression of the target and poor prognosis. We knew then this may be a game changer for ovarian cancer because it was present in all major subtypes. We saw the potential for a novel biomarker and an associated target. We developed TTX335o to specifically target LMTK3 pathways that kill tumors without harming normal cells, even at high doses.”
“Treatment with TTX335o and other modalities, like siRNA, significantly induced the killing of both chemosensitive and chemoresistant ovarian cancer cells without affecting normal cells in vitro,“ said Anna Portela, CEO of Xenopat, a spin-off of the Catalan Institute of Oncology (ICO), the Bellvitge Biomedical Research Institute (IDIBELL), and the Bellvitge University Hospital (HUB). “Moreover, we observed this killing as synergistic with both Cisplatin and Taxotere treatment in vitro. We used an A2780 cell line-derived orthotopic xenograft mouse model of ovarian cancer to test the efficacy of specific TTX335o in vivo. Strikingly, TTX335o 20 mg/kg IV dose given in the same dosing schedule and duration as cisplatin showed a 35% tumor reduction. More importantly, in vivo safety studies showed no signs of toxicity of TTX335o, even at a very high dose of 40 mg/kg. With molecule, dose, and schedule optimization in ongoing experiments, we could expect a higher efficacy.”
“We have generated a substantial amount of preclinical data demonstrating TTX335o is unlike any other targeted therapy for ovarian cancer or approach,” said Dr. Neil Sankar, Chief Medical Officer at Temple Therapeutics. “The addition of a companion diagnostic for early detection, therapeutic impact, and disease progression injects much-needed hope for ovarian cancer patients. Earlier diagnosis and intervention improve patient outcomes. It seems that this target is agnostic across the major histological subtypes which helps to serve the 80% of ovarian cancer patients who do not have the BRCA genes (BReast CAncer).”
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