BACKGROUND: More than 7 million new cases of cancer diagnosed each year benefit from radiation therapy (RT) but recurrences still occur, suggesting an intrinsic tumor radioresistance. Furthermore RT has been shown to sustain Cancer Stem Cells (CSCs) and cancer-associated fibroblasts (CAF) populations that actively participate in RT resistance. Whether high dose of RT (HDR) could kill CSCs and CAF cells, the risk of inducing acute/late side effects strongly recommend the use of low doses of RT (LDR) that, in combination with radiosensitizing agents, could kill tumor and tumor-derived cells without side effects. Microtubule Targeting Agents (MTAs) are important chemotherapeutics and radiosensitizers agents. This project wants to exploit and optimize a focused library of MTAs based on a proprietary scaffold (PBOX) and innovative radiosensitizers identified from marketed drugs to explore pioneering radiosensitizing therapeutic strategies.
MATERIALS and METHODS: Patient-derived primary tumor and CAF cells will be generated from prostate, endometrium, cervical, rectal, breast and head and neck tumors. A library of optimized PBOXs will be designed in silico using specific software, focusing on affinity for tubulin and drug-like properties. In vitro and in vivo RT will be performed using Helical Tomotherapy (HT) coupled with an in-house phantom that will permit us to deliver at the same time different radiation doses to several flasks or xenografted mice. Several in vitro and in vivo assays will be performed.
RELEVANCE OF THE PROJECT: The public health implications of this study are substantial. Testing our hypothesis is of pivotal importance. The investigation of PBOXs in combination with LDR, the analysis of their effects at the molecular leve will offer the possibility to better undestand the molecular mechanisms of radioresistance and to known drugs as radiosensitizers for a direct translation to clinic.
More than 14 million new cases of cancer are diagnosed globally each year and approximately 50% benefit from radiation therapy (RT) used to cure several types of cancers. Despite delivery radiation is subjected to continuous improvements, the risk of recurrence remains high, suggesting an intrinsic cancer cells radioresistance. Considering that the prevalence of cancer survivorship is expected to be even larger in the future because of the aging and growth of the population and of improved survival following diagnosis due to advances in screening, detection, and treatment, the number of patients that will experience a cancer recurrence is destined to increase. Beyond reducing overall survival and drastically affecting the quality of life, cancer recurrence represents an important social and economic problem. Accordingly, several estimations of the economic burden of cancer recurrence clearly show the magnitude of the problem. Tumor recurrences involve health care expenditures, productivity loss and morbidity for patients and their families that ultimately affect the entire population at the social level. Patients experiencing cancer recurrence require more costly care than patients who did not develop recurrent disease; thus, reducing the number of patients with tumor recurrence leads to a net gain for the whole society. Considering the prevailing role of radiotherapy in cancer recurrence treatment, the public health implications of this project are substantial. The identification of new therapeutic strategies able to increase responsiveness to radiation therapy, thus reducing the risk of the recurrence, may significantly reduce the costs. To this purpose, it is necessary to identify a therapeutic approach able to kill cancer cells, stem and non-stem cells, and all other non-tumor cells actively participating in tumor maintenance. Increasing evidences support the use of Low Dose Radiation (LDR) regimens as an adjuvant anticancer treatment. LDR spare healthy tissues, do not promote secondary radio-induced tumors and promote immunostimulatory effects providing local tumor control. Whether the therapeutic role of LDR is unquestionable, it is necessary to identify new radiosensitizing strategies that, without affecting normal tissues homeostasis, can drastically enhance the therapeutic effect of LDR. In this regard, our proposal is focused on a novel therapeutic strategy envisaging the use of LDR in combination with innovative radiosentisizers to effectively kill cancer cells. This strategy would abolish the issues related to the harmful side effects of high doses radiation used in cancer treatment. To this regard, drugs showing radiation enhancement in the medium- low-dose range, that is, the size of the dose-per fraction of conventionally fractionated RT (typically 2Gy), should be further investigated in the preclinical setting. The most updated RT technology has the inconvenience of a widespread deposition of such small doses to large amounts of healthy tissues. Experiments on normal cells could shed more light on the mutagenic effects of combining irradiation with these sensitizing drugs, in order to explore a possible impact on treatment-related induction of new cancers. Radio-sensitizing agents suitable to overcome cancer heterogeneity and not significantly impairing healthy tissue radiation tolerance, deserve the utmost interest for radiobiological investigation. In particular, this project will rely on potent innovative radiosensitizers including microtubule targeting agents PBOX compounds (MTAs-PBOXs), and ad-hoc identified marketed drugs through a focused repositioning approach. The preliminary data on the first generation of MTAs-PBOXs support the feasibility of this research plan. The proposed experimental approach will benefit of an in-house dosimetry phantom for irradiation in electronic equilibrium which will allow irradiation conditions very close to clinical RT, simultaneously treating several flasks with several radiation doses, and drastically reducing the experimental variability. Overall, this proposal will finally provide a solid proof-of-concept for the use of potent radiosentisizers in combination with LDR as a strategic treatment to fight resistant, highly aggressive types of cancers.