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Yaromina, A.

Publications and source records attributed to Yaromina, A..

2 recordsLinked to original sources
bioRxiv2025

Deficiencies in the Fanconi Anemia or the Homologous Recombination Pathway enhance the antitumor effects of the novel hypoxia-activated prodrug CP-506

The novel hypoxia-activated prodrug CP-506 has been shown to selectively target hypoxic tumor cells, which are associated with disease progression and resistance to conventional anti-cancer therapies. Given the alkylating effector metabolites, we hypothesize that defects in interstrand crosslink (ICL) and double strand break (DSB) DNA repair may serve as a predictive biomarker of sensitivity to CP-506. Here, we evaluated the role of DNA damage repair pathways in the antitumor response to CP-506. Isogenic cancer cell lines proficient or deficient in the Fanconi Anemia (FA), homologous recombination (HR), or non-homologous end joining (NHEJ) pathway were cultured as 2D monolayers and 3D spheroids. Cell viability, clonogenic cell survival, and spheroid growth inhibition were assessed following CP-506 exposure. Mice bearing subcutaneous isogenic xenografts received CP-506 (600 mg/kg; QD5) or vehicle treatment upon reaching a tumor starting volume (SV) of 244.9 {+/-} 72.0 mm3. Treatment response was quantified as time to reach 4xSV (T4xSV) and respective enhancement ratios (ER), defined as T4xSVCP-506/T4xSVvehicle. DNA damage and repair capacity were evaluated by {gamma}H2AX and alkaline comet assays. In vitro, cell lines deficient in FA or HR, but not NHEJ, showed enhanced sensitivity to CP-506 compared to parental cells in viability and clonogenic assays. This was confirmed in spheroid growth inhibition studies. In vivo, the antitumor response to CP-506 was more pronounced (P<0.0001) in LNCaP AR FANCA-/- (ER 4.0{+/-}1.1) and LNCaP AR FANCD2-/- (ER 3.4{+/-}0.8) xenografts compared to parental LNCaP AR (ER 1.5{+/-}0.5) xenografts. CP-506 treatment of DLD-1 BRCA2-/- (2.9{+/-}0.7; P<0.0001) xenografts resulted in significantly enhanced ER compared to parental (1.3{+/-}0.2) xenografts. Similar results were obtained in HCT116 BRCA2-/- (ER 4.0{+/-}0.6; P<0.0001) versus parental (ER 1.7{+/-}0.6) xenografts. In contrast, the ER of HCT116 DNA-PKcs-/- (1.4{+/-}0.3; P=0.18) xenografts was not different from HCT116 parental xenografts. Under anoxic conditions, CP-506 caused elevated {gamma}H2AX foci counts in FANCA-(2.0-fold increase at 48 hours) and FANCD2-deficient cells (1.4-fold increase at 72 hours) compared to LNCaP AR parental cells (P<0.0001). Similarly, {gamma}H2AX expression was increased in DLD-1 BRCA2-/- cells, but not in HCT116 BRCA2-/-cells, compared to their respective parental cells. In xenografts, FA- and HR-deficiency caused elevated {gamma}H2AX expression compared to respective parental tumors (1.6-9.3-fold increase). HCT116 DNA-PKcs-/- cells and xenografts displayed reduced {gamma}H2AX expression compared to their parental counterpart, with an 0.5-fold reduction. The comet assay confirmed CP-506-induced ICLs and DNA strand breaks but was unable to explain the differential therapeutic responses of CP-506 among isogenic tumor cells. Deficiencies within FA or HR, but not NHEJ, enhanced the antitumor effects of CP-506 through a mechanism consistent with the concept of synthetic lethality. Therefore, both DNA repair status and the presence of tumor hypoxia represent key biomarkers for patient stratification in clinical trials of CP-506.

cancer biology↗
bioRxiv2019

Combining Hypoxia-Activated Prodrugs and Radiotherapy in silico: Impact of Treatment Scheduling and the Intra-Tumoural Oxygen Landscape

Hypoxia-activated prodrugs (HAPs) present a conceptually elegant approach to not only overcome, but better yet, exploit intra-tumoural hypoxia. Despite being successful in vitro and in vivo, HAPs are yet to achieve successful results in clinical settings. It has been hypothesised that this lack of clinical success can, in part, be explained by the insufficiently stringent clinical screening selection of determining which tumours are suitable for HAP treatments. Taking a mathematical modelling approach, we investigate how tumour properties and HAP-radiation scheduling influence treatment outcomes in simulated tumours. The following key results are demonstrated in silico: (i) HAP and ionising radiation (IR) monotherapies may attack tumours in dissimilar, and complementary, ways. (ii) HAP-IR scheduling may impact treatment efficacy. (iii) HAPs may function as IR treatment intensifiers. (iv) The spatio-temporal intra-tumoural oxygen landscape may impact HAP efficacy. Our in silico framework is based on an on-lattice, hybrid, multiscale cellular automaton spanning three spatial dimensions. The mathematical model for tumour spheroid growth is parameterised by multicellular tumour spheroid (MCTS) data. Author SummaryWhen cancer patients present with solid tumours, the tumours often contain regions that are oxygen-deprived or, in other words, hypoxic. Hypoxic cancer cells are more resistant to conventional anti-cancer therapies, such as chemotherapy and radiotherapy, and therefore tumour hypoxia may complicate treatments. Hypoxia-activated prodrugs constitute a conceptually elegant approach to not only overcome, but better yet, exploit tumour hypoxia. Hypoxia-activated prodrugs are drugs that act as Trojan horses, they are theoretically harmless vehicles that are converted into warheads when they reach their targets: hypoxic tumour cells. Despite being conceptually clever and successful in experimental settings, hypoxia-activated prodrugs are yet to achieve successful results in clinical trials. It has been hypothesised that this lack of clinical success can, in part, be explained by an insufficiently stringent clinical screening selection of determining which tumours are suitable for hypoxia-activated prodrug treatments. In this article, we investigate how simulated tumours with different oxygen landscapes respond to anti-cancer treatments that include hypoxia-activated prodrugs, either alone or in combination with radiotherapy. Our simulation framework is based on a mathematical model that describes how individual cancer cells in a tumour divide and respond to treatments. We demonstrate that the efficacy of hypoxia-activated prodrugs depends on both the treatment scheduling, and on the oxygen landscape of the specific, simulated tumour.

cancer biology↗