Pre-radiotherapy identification of individual genomic profile to avoid, by resort to customized radiosensitizers, the risk of radioresistance development in patients with localized prostate cancer

To the Editor,

In the Bristow et al¹ study, prostate cancer (CaP)-related genomic predictors of prognosis and radiotherapy response are carefully taken into consideration, together with hypoxia-affected cancer microenvironmental conditions. Particularly, pre-treatment DNA/RNA-based genomic tests as well as assays reflecting hypoxia-influenced cancer metabolism behaviour are the subject of a proven thorough research.

Looking to further CaP genomic profile assessments to reach a more customized radiation therapy against a possible development of cancer radioresistance, other approaches may be highlighted. The identification, indeed, of gene aberrations responsible for either the hyperactivation of cancer cell proliferation signalling pathways, such as phosphatidylinositol 3-kinase (PI3K)-Akt/mammalian target of rapamycin (mTOR), mitogen-activated protein kinase (MAPK) and signal transducer activator of transcription (STAT), or, instead, the evasion of apoptosis signalling pathway—from caspase sequence machinery to proteolytic cleavage of poly-adenosine diphosphate ribose polymerase-1 (PARP-1) with following DNA fragmentation—may lead to them being targeted by specific radiosensitizer agents, among which NVP-BEZ235 or SB203580 (respectively, inhibitors of the PI3K-Akt/mTOR or MAPK pathways), AG490 to block STAT3, HA14-1(opposed to the antiapoptotic Bcl-2), olaparib as a PARP-1 blocker and LCL521/385 to target acid ceramidase proteolytic degradation promoters.^2,3

Regarding genomic predictors of radiation therapy response, a particular significance is today also recognized with regards to the prostate cancer stem cell (PCSC) genes, that are often responsible for the CaP radio- and/or chemoresistance development by enhancing cancer cell proliferation and supporting cancer cell death evasion. Indeed PCSCs, by ATR (ataxia telangiectasia-mutated/Rad-related kinase proteins) gene-mediated DNA repair mechanisms, make sure of their own survival against ionizing radiation. Moreover, the specific gene mutation-dependent overactivation of PCSC self-renewal pathways—such as Wnt/β-catenin, Hedgehog and Notch pathways—play an important role in facilitating the radioresistance development. In this regard, perifosine, besides inhibiting Akt/cytoskeletal signalling pathway, can also block the Wnt one following tumour radiosensitization. In addition, CXCR4 (CXC motif receptor 4) chemokine has been recently identified as a biomarker for both drug- and radioresistant cancer stem cells, given that its interaction with the specific ligand CXCL12 can protect them from anticancer agents and radiation. It follows that a feasible block of such interaction could represent a promising chance to improve the CaP radiation therapy.⁴

Intriguingly, the inherited variation of single nucleotide polymorphism (SNP) in ribonuclease L (RNASEL) gene—rs 12757998 variant allele in chromosome 1q25—can affect organ-confined CaP outcome after external beam radiation therapy, given its association with increased circulating C-reactive protein and interleukin-6 that play a potential role in inflammatory response to radiation following tumour cell apoptosis. Hence, low inflammatory RNASEL SNP rs 12757998 gene-dependent protein levels seem to be responsible, instead, for the CaP cell apoptosis decrease-induced radioresistance.⁵

With high esteem towards Bristow et al's¹ research work, it is foreseeable that more and more detailed pre-radiotherapy CaP genomic profile assessment—in the field of properly customized healthcare—might allow, by a possible resort to suitable personalized radiosensitizer measures, favourable radiation therapy optimization opportunities to be reached.⁶