Periodic Reporting for period 1 - PACT4EYE (Innovative Photoactivated Ruthenium Chemotherapy to treat eye cancer)
Période du rapport: 2023-11-01 au 2024-10-31
Ruthenium-based photoactivated chemotherapy (PACT) is a new technology where the toxicity and anticancer activity of a chemotherapy drug is tuned down by attaching a molecular “cage” to the chemotherapy molecule. By doing so, the active but toxic chemotherapy drug is transformed into a prodrug that is both inactive and non-toxic for the patient. After giving such a prodrug to the patient, for example intraveinously, the prodrug distributes in the body and, like any other drug, partly penetrates into the tumor where it does not do anything. A light source is then used to shine light onto the tumor, where the molecular “cage” is photochemically removed, thereby recovering the anticancer activity of the chemotherapy drug. Local activation of the prodrug ensures a low systemic toxicity of the treatment for the patient, and hence low side effects, compared to standard chemotherapy that is already active when injected in a patient.
Though in theory applicable to all forms of cancer, PACT is not yet applied in the clinics. The ambition of PACT4EYE is to develop the clinical potential of one particular prodrug of this kind, which has been developed at Leiden University, in the context of uveal melanoma (UM). UM is the most common form of eye cancer but it is a rare disease. It hence represents a challenging target for drug development and for the translation of new molecules to the clinics, as big pharma is typically not interested. On the other hand, special regulations have been developed in Europe to simplify the translation of innovative treatments of rare diseases.
The ambition of PACT4EYE is to use this simplified path to demonstrate to science, to the public, and to investors, that it is possible to develop PACT treatment of UM as an industrially viable product. Our target is to define such a product, and to develop a realistic business plan towards development of this product towards clinical trial. Our consortium will define our clinical target and product, and perform all pre-clinical work necessary to demonstrate the safety and efficacy of our prodrug in animal models using patient-derived tumor models. These tumor models currently represent the method with the best predictive power for the clinical success of new (pro)drugs.
The project includes a chemical part for scaling up synthesis and preparing it for GMP production; a biological part, to study toxicity of our prodrug towards animals, their eyes, and their vision, and the efficacy of our treatment in tumor models; and a business part, to investigate the patent landscape, develop a business plan and the business readiness of our product.
Though in theory applicable to all forms of cancer, PACT is not yet applied in the clinics. The ambition of PACT4EYE is to develop the clinical potential of one particular prodrug of this kind, which has been developed at Leiden University, in the context of uveal melanoma (UM). UM is the most common form of eye cancer but it is a rare disease. It hence represents a challenging target for drug development and for the translation of new molecules to the clinics, as big pharma is typically not interested. On the other hand, special regulations have been developed in Europe to simplify the translation of innovative treatments of rare diseases.
The ambition of PACT4EYE is to use this simplified path to demonstrate to science, to the public, and to investors, that it is possible to develop PACT treatment of UM as an industrially viable product. Our target is to define such a product, and to develop a realistic business plan towards development of this product towards clinical trial. Our consortium will define our clinical target and product, and perform all pre-clinical work necessary to demonstrate the safety and efficacy of our prodrug in animal models using patient-derived tumor models. These tumor models currently represent the method with the best predictive power for the clinical success of new (pro)drugs.
The project includes a chemical part for scaling up synthesis and preparing it for GMP production; a biological part, to study toxicity of our prodrug towards animals, their eyes, and their vision, and the efficacy of our treatment in tumor models; and a business part, to investigate the patent landscape, develop a business plan and the business readiness of our product.
In WP1 (chemistry), we obtained our main inhibitor from a CDMO and realised in our laboratories the first large scale synthesis of our photocaged lead compound (10 g).
In WP2 (biology, ectopic models), we amplified in mice a range of patient tumor materials with different genetic background, to be able to study the antitumor effect and toxicity of our lead PACT compound in zebrafish embryo tumor models. The aim is to screen different patient-derived tumors and to study the response of these different tumors to our lead compound, to identify the genetic profile of the tumors that respond best to the treatment. The zebrafish tumor model study currently running and will be communicated in a deliverable towards the middle of the project. We already discovered that BAP1 status of the tumor influenced the rate of the response of the cancer cells to our compound, but also that PACT treatment with our compound could attack both BAP1+ and BAP1- cells.
In WP3 (biology, orthotopic models), we developed an orthotopic model of uveal melanoma by groiwn patient-derived primary eye tumors in mice. This model will be used in the RP2 of the project to study the efficacy and safety of our lead compound, once we have found in WP2 which tumor responds best to the treatment.
In WP4 (product definition), we investigated several formulations of our lead compound, and showed that some formulation had a positive influence on the light activation of our lead compound in vitro. We also tested the biodistribution of some of these formulation in a subcutaneous mice tumor model and found a formulation that is safe and provides good tumor uptake of our compound.
In WP2 (biology, ectopic models), we amplified in mice a range of patient tumor materials with different genetic background, to be able to study the antitumor effect and toxicity of our lead PACT compound in zebrafish embryo tumor models. The aim is to screen different patient-derived tumors and to study the response of these different tumors to our lead compound, to identify the genetic profile of the tumors that respond best to the treatment. The zebrafish tumor model study currently running and will be communicated in a deliverable towards the middle of the project. We already discovered that BAP1 status of the tumor influenced the rate of the response of the cancer cells to our compound, but also that PACT treatment with our compound could attack both BAP1+ and BAP1- cells.
In WP3 (biology, orthotopic models), we developed an orthotopic model of uveal melanoma by groiwn patient-derived primary eye tumors in mice. This model will be used in the RP2 of the project to study the efficacy and safety of our lead compound, once we have found in WP2 which tumor responds best to the treatment.
In WP4 (product definition), we investigated several formulations of our lead compound, and showed that some formulation had a positive influence on the light activation of our lead compound in vitro. We also tested the biodistribution of some of these formulation in a subcutaneous mice tumor model and found a formulation that is safe and provides good tumor uptake of our compound.
Our newly developed orthotopic PDX model of primary UM in mice is beyond state of the art; only very few worlwide can do that. Our large-scale synthesis of a PACT ruthenium complex is also one of its kind.
Our key needs is some advice on IP strategy and patent landscape analysis, as well as some regulatory advice to establish a “quality target product profile” (QTPP).
Our key needs is some advice on IP strategy and patent landscape analysis, as well as some regulatory advice to establish a “quality target product profile” (QTPP).