Novel Intracellular Approach to Combat Renal Cancer: Targeting the Tumour Adaptation Mechanism Under Anti-Angiogenic Therapy
Renal cell carcinoma (RCC) represents a significant cancer challenge, accounting for approximately 3.8% of all new cancer cases, with about 430,000 new diagnoses and 180,000 deaths annually worldwide. Alarmingly, 35% of patients present with metastatic RCC, and require aggressive treatment. The current standard of care predominantly relies on anti-angiogenic regimens as first and second line treatments. Anti-angiogenic treatments are aimed at preventing blood vessel formation into the tumour, shutting down oxygen and nutrient supply and reducing metastatic risk. Approximately 20% of patients do not respond to anti-angiogenics and of the patients that initially respond, a staggering 70% of patients experience the development of tumour resistance. Tumour resistance renders these anti-angiogenic treatments ineffective over time, contributing to a distressingly low five-year survival rate of ~13% for late-stage RCC patients. Consequently, there is a substantial unmet clinical need for innovative treatments capable of managing drug resistant RCC.
The NIAC project will expedite the development of a novel Tumor Adaptation inhibitor for treating drug-resistant advanced RCC. This TA-1 inhibitor has anti-tumour properties as TA-1 is crucial for tumour growth and resistance to anti-angiogenic treatment, as identified by AtgTX's Tumour Adaptation Target Identification platform (TACTIC). Combining the TA-1 inhibitor with anti-angiogenic treatment will enhance the anti-tumour effect. Preclinical data also shows the TA-1 inhibitor's anti-tumour effect as a standalone agent in tumours resistant to anti-angiogenic treatment that express TA-1. This effort includes generating renal organoid models from patient biopsies, optimizing culture conditions, conducting viability and cytotoxicity screenings, and performing chemosensitivity screenings on ex vivo explants. The goal is to deepen our understanding of RCC subtypes through sophisticated molecular analyses, and to validate the potential therapeutic compounds in near-patient models guided by specific biomarkers, thereby facilitating the selection of the most promising leads for future clinical development.
This project is funded by the #5995 NIAC Eurostars Consortium project (co-PI, main PI Prof.M.Kruithof-de Julio).
Fetal microchimerism- a proxy model for cancer cell homing and micrometastasis?
Lack of screening tools of patients in remission for risk of cancer relapse and metastasis remains a major challenge in biomedicine. There is increased need for experimental models that capture the process of cells surviving in distant organs and thriving or expanding upon favourable conditions. Often, metastases manifest years after primary cancer diagnosis and treatment, a phenomenon attributed to cancer cell dormancy and micrometastasis. For instance, prostate and breast cancers have high incidence of non-synchronous bone metastases. Yet the complications due to metastasis are the main contributors to mortality in all cancer types. The disruption of tissue architecture and function due to the presence of foreign cells is associated with metastasis impact. However, if exchange of foreign cells across tissues is linked to pathological situations why is our organism unable to detect them? In fact, exchange of cells among different organs and tissues is not so uncommon, for instance, osteocytes migrate to damaged organs, hematopoietic stem cells in the bone marrow repopulate all blood cell lineages, endometriosis and even fetal-maternal cell exchange. We are investigating whether the mechanisms that govern non pathological cell exchange such as fetal microchimerism into bone marrow for prolonged periods, share similarities with cancer cell migration and dormancy.
The project is funded by the SNF SPARK (CRSK-3_228930, 2024, main PI).
