In vivo Pharmacological Validation of Nanopharmaceutic Inhibitors of ROCK2 in Metastatic Breast Cancer and Spinal Cord Injury (INNVAL10/19/0467)

Funding Agency: Valencian Agency of Innovation

 

The main objective of the work presented in this proposal is the evaluation of a nanopharmaceutical ROCK inhibitor comprising Fasudil conjugated to poly-l-glutamic acid (PGA) in relevant preclinical models. We aim to explore the single-agent and combination therapies in the treatment of two pathologies – advanced stage spinal cord injury and triple-negative breast cancer (TNBC).

This nanopharmaceutical (PGA-FAS) has provided very promising results in both in vitro models of breast cancer and in vivo models of spinal cord injury when combined with cell therapy (neural progenitor/precursor cells). The further evaluation of this new nanopharmaceutical in these two different pathologies will be supported by two research groups at the Centro de Investigación Príncipe Felipe – the Polymer Therapeutics Laboratory led by Dr. Maria Jesus Vicent and the Neuronal and Tissue Regeneration Laboratory led by Dr. Victoria Moreno

The current proposal involves carrying out the preclinical assays required for the commercial/clinical exploitation of the new nanoconjugate and for a patent in the two noted pathologies.

  1. Spinal Cord Injury – The translation of the preclinical trials that demonstrated the neural regenerative effect of the combination of PGA-FAS and rat neural precursor transplantation in experimental models of spinal cord injury to the application of human neural precursors.
  2. Cancer – We aim to evaluate the anti-tumor and anti-metastatic capacity of the PGA-FAS conjugate in vivo in an MDA-MB231Luc2 mouse model of TNBC that has been developed in our laboratory. Furthermore, the development of tumor organoids derived from TNBC patients will bring the relevance of this study closer to clinical reality and provide greater translational value for our nanopharmaceutical. Finally, we will study the antitumoral activity of PGA-FAS in combination with Dinaciclib in organoid models to explore potential anti-tumor synergism and augmented therapeutic efficiency. Of note, this combination has already demonstrated efficacy in cell models.