ESTRO 2020 Abstract book

S74 ESTRO 2020

SP-0137 Personalized medicine in the context of hypoxia-directed therapy B. Wouters 1 1 Princess Margaret Cancer Centre- University Health Network, Toronto, Canada Abstract text Hypoxia has been demonstrated to limit the effectiveness of radiation therapy and has stimulated the development of numerous therapeutic approaches to improve patient outcome. However, despite numerous phase 2 and even phase 3 trials, no hypoxia targeted therapies have been approved and implemented into clinical practice. This is due in part to the fact that hypoxia is a dynamic property of the tumour microenvironment and highly variable across patient populations. The development of hypoxia within an individual tumour is also related to multiple factors. For many years, the variation in hypoxia across patients was attributed largely to tumor specific abnormalities in oxygen delivery associated with immature or incomplete vascularization. However, more recently it has become clear that cancer associated mutations drive also drive changes in cellular metabolism leading to variation in oxygen consumption and oxygen demand. Furthermore, levels of hypoxia are influenced by tumor specific differences in hypoxia tolerance and adaptation. Cancer cells adapt to low hypoxia through a complex series of cellular changes that influence metabolism and resistance to cell death. To date, the approaches to target hypoxia in the clinic have ignored patient specific attributes not only in overall levels of hypoxia, but also in the underlying drivers of hypoxia within individual tumors. Future clinical development and testing of new approaches to target will need to select not only patients with hypoxic tumors, but also will need to use approaches that are designed to address the rate limiting cause of hypoxia. Examples of paths forward targeting oxygen metabolism and hypoxia tolerance will be discussed. SP-0138 Hypoxia-activated prodrug combination therapies M. Pruschy University of Zurich, Zurich, Switzerland SP-0139 Oligometastatic state: definition, diagnosis and prognosis B.A. Jereczek-Fossa 1 1 Università degli Studi di Milano - European Institute of Oncology, Oncology&hemato-oncology Dept/Radiotherapy Dept. of European Institute of Oncology, Milan, Italy Abstract text Modern imaging has changed the spectrum of prostate cancer (PC). The tree main categories: organ confined, locally advanced and metastatic PC have been diversified based on the risk categories (for organ confined, locally advanced PC) or volume of the disease (low volume and high volume). Moreover, metastatic PC can be divided in de novo e recurrent metastatic PC and, based on the castration-sensitivity in castration sensitive (hormone sensitive) and castration resistant PC. Therefore, there are numerous criteria for metastatic PC definition (disease volume, time of metastases occurrence, hormonal- sensitivity status). This underlines the extremely wide variability (heterogeneity) of the metastatic PC. Volume based definitions are also heterogenous, the Advanced Prostate Cancer Consensus Conference (APCCC) showed Abstract not received Symposium: Multimodal approaches in oligometastatic prostate disease: state-of-the-art

Symposium: Hypoxia-activated prodrugs: is there a future?

SP-0135 Hypoxia-activated prodrugs: why haven´t promising preclinical results translated to the clinic? A. Salem 1 1 University of Manchester, Division of Cancer Sciences, Northwich, United Kingdom Abstract text Tumour oxygen deprivation (hypoxia) is associated with radioresistance and poor survival. Targeting hypoxia using hypoxia-activated prodrugs is an attractive idea. However, to date, the promising preclinical results of hypoxia- activated prodrugs have not translated into patient benefit in the clinic with a number of failed phase III trials. In this presentation, I will explore the likely reasons why these trials were negative. Specifically, I will highlight 3 salient points: (1) the importance of patient selection using hypoxia biomarkers; (2) the need to ensure radiotherapy quality assurance; and (3) the hope for developing more effective hypoxia-activated prodrugs. I will use these to make recommendations on how to design future successful hypoxia-targeted drug trials. SP-0136 Off target effects with hypoxia activated prodrugs: lessons learned from PR-104A A. Mowday 1 , L. Dubois 1 , J. Smaill 2 , A. Patterson 2 , P. Lambin 1 , J. Theys 1 1 maastricht University, Precision Medicine, Maastricht, The Netherlands ; 2 university Of Auckland, Auckland Cancer Society Research Centre, Auckland, New Zealand Abstract text Tumour hypoxia has long been recognised as an important issue in oncology. However, despite over 40 years of pre- clinical and clinical research hypoxia is still yet to be successfully exploited therapeutically in humans. The main targeting strategy has been to use hypoxia activated prodrugs (HAPs), designed to release a cytotoxic agent within hypoxic tumour regions whilst sparing normal healthy tissue from damage. In general, HAPs achieve tumour selectivity by being inert prodrugs that require enzymatic reduction (primarily by oxidoreductases) in order to release or activate the cytotoxic effector. In such a process, one-electron reduction generates a prodrug radical species that can be back-oxidised in the presence of oxygen to the parental prodrug. In the absence of oxygen, the prodrug radical can be further reduced or fragmented to generate the active cytotoxic metabolites. Although this approach can potentially be highly selective, off target activity can occur, most commonly from two- electron reduction by oxygen insensitive enzymes directly to the cytotoxic product. The HAP PR-104A is one such example. Originally designed as a potent bioreductive HAP, PR-104A was ultimately found to have off-target activity from the aerobic two-electron reductase AKR1C3 (aldo-keto reductase family 1 member C3). It is possible that AKR1C3 expression in normal CD34 + myeloid progenitor cells is responsible for the dose-limiting myelosuppression that restricted the exposure of PR-104A in humans to approximately 15% of that achievable in pre- clinical mouse models. This presentation will use PR-104A as an example of how an off-target effect of a HAP can be either exploited, eliminated by modification of the prodrug scaffold, or re-purposed for an alternative use. It will also discuss whether activation of HAPs at relatively mild levels of hypoxia can be considered an off-target effect, and the implications of this phenomenon on drug activity.

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