Palladium-activated prodrug therapy: a novel focal therapy for localised cancers of unmet need

Despite significant advances in the diagnosis and treatment of the earliest stages of cancer, the highest life-threatening risks and therapeutic challenges still remain in developing effective treatment of patients diagnosed with locally advanced or metastatic tumours. For most localised tumours the current treatment is surgical resection, often followed by adjuvant radiotherapy and/or chemotherapy. The potential benefit of such therapies in any stage of the cancer must be weighed against possible adverse effects that can severely impair a patient's quality of life. Unfortunately, even with adjuvant chemotherapy to treat some aggressive cancers like glioblastoma multiforme, the median survival is only improved around 2 months, while associated side effects are very severe. In addition, for localised prostate cancer, significant controversy remains on the optimal treatment options. Due to side effects (incontinence, impotence, bowel problems) of existing treatments (surgery or radiotherapy), current standard of care is active surveillance consisting of regular hospital tests (e.g. prostate biopsies and MRI scans), aimed at deferring intervention. Because of the lack of therapies providing a better balance between treatment efficacy and related toxicities, many of these cancers eventually evolve into a more aggressive form with increased risk of pre-mature death. Therefore, what is needed then are novel drug delivery strategies that can reduce the side effect profile of the treatment whilst maximising therapeutic efficacy.
To provide a safer and more effective strategy to those localised cancers, we have devised a novel therapeutic approach that will allow concentrating drug activity only at the cancer area, thereby reducing the severe adverse effects associated with chemotherapy. The technology is based on a novel strategy pioneered at the Edinburgh Cancer Research Centre at the University of Edinburgh that enables full control over where chemotherapy takes action through the use of solid metal devices made of an element called palladium. This metal, which is completely safe to patients (it is already employed in dentistry), can be shaped into implantable devices and possesses exceptional chemical properties that facilitate the local release of anticancer drugs. By implantation inside localised tumour, orally-given drug precursors will only become "active" at the cancer site upon interaction with the palladium device. Given the reusability of this device, this treatment could be repeated as many times as necessary. The unique modulatory capabilities of this novel approach will not only reduce drug presence in healthy organs but will also facilitate personalized treatments to be implemented according to the progression and severity of the disease, thereby reducing side effects and maximizing the efficacy of the therapy. Due to its novelty, such healthcare technology will make a major impact in the Pharma sector and, in turn, in the NHS and people of the UK and worldwide by improving the quality of life and life expectancy of patients suffering from untreatable tumours.

(1) Impact in Healthcare. The proposed research programme aims to develop a novel drug release technology that will benefit cancer patients by enhancing efficacy and reducing side effects of chemotherapy. Specifically, it will provide a first-line therapy for patients diagnosed with locally-advanced primary tumours, such as localised prostate cancer and glioblastoma multiforme, two unmet clinical needs with >25,000 new diagnosed cases per year just in the UK. The proposed strategy significantly differentiates from other technologies enabling focal treatment of disease (e.g. photodynamic therapy, brachytherapy or controlled-release implants) because -unlike those- it will enable multidose regimes and easy dose regulation by controlling the quantity of prodrug administered. In addition, this research programme will allow exploiting the benefits of this novel approach with a variety of chemotherapeutics with different mode of actions to appropriately tailor the treatment to different cancers and stages. These advantages will facilitate responsive treatments to be implemented in a personalized manner according to the progression and severity of the disease.
(2) Impact in Economy. Novel IP may be generated and commercially exploited due to the originality and potential medical impact of such a technology in the Pharma sector. Early engagement with a VC group (Epidarex), mediated by UoE's Tech offices, has provided a defined route map to attract private funds and support the translation of the technology into the clinic: strong preclinical validation with demonstrated efficacy and safety to treat each cancer indication in clinically relevant animal models. Consequently, we have formed a multidisciplinary team that includes prostate cancer surgeon Prof Heung and neurosurgeon Dr Brennan, who will support the preclinical and clinical validation of the technology. Once the strategy has been validated in vivo, engagement with VC / Pharma will be pursued further to form a commercialization vehicle (start-up or collaborative venture) and progress the technology into human trials. A sound infrastructure exists to support commercialization: Edinburgh Research & Innovation and Edinburgh BioQuarter (UoE and College of Medicine's technology offices, respectively) will support IP protection and licensing; will provide advice and mentoring for the creation of spin-out companies; and links to Pharma / investors that would allow further development opportunities. Importantly, besides the University's track record in IP commercialisation, the PI has significant experience in this sector as inventor of 6 patents for a variety of technologies and co-founder of 2 spin-out companies.