Abstract
Karonudib (TH1579) is a novel compound that exerts anti-tumor activities and has recently entered phase I clinical testing. The aim of this study was to conduct a pre-clinical trial in patient-derived xenografts to identify the possible biomarkers of response or resistance that could guide inclusion of patients suffering from metastatic melanoma in phase II clinical trials. Patient-derived xenografts from 31 melanoma patients with metastatic disease were treated with karonudib or a vehicle for 18 days. Treatment responses were followed by measuring tumor sizes, and the models were categorized in the response groups. Tumors were harvested and processed for RNA sequencing and protein analysis. To investigate the effect of karonudib on T-cell-mediated anti-tumor activities, tumor-infiltrating T cells were injected in mice carrying autologous tumors and the mice treated with karonudib. We show that karonudib has heterogeneous anti-tumor effect on metastatic melanoma. Thus, based on the treatment responses, we could divide the 31 patient-derived xenografts in three treatment groups: progression group (32%), suppression group (42%), and regression group (26%). Furthermore, we show that karonudib has anti-tumor effect, irrespective of major melanoma driver mutations. Also, we identify high expression of ABCB1, which codes for p-gp pumps as a resistance biomarker. Finally, we show that karonudib treatment does not hamper T-cell-mediated anti-tumor responses. These findings can be used to guide future use of karonudib in clinical use with a potential approach as precision medicine.
Highlights
Cutaneous melanoma is the most aggressive form of skin cancer and is often fatal in metastatic stages[1]
Individual growth curves are shown in supplemental figures S2S4. f Kaplan–Meier graph showing the comparison of probability of progression-free survival in karonudib-treated mice for the three response groups, Mantel–Cox test used for statistical analysis. g Quantification of immunohistochemical staining for the proliferation marker Ki-67 in vehicle vs. karonudib-treated PDXes, Student’s t test showing statistically significant difference between the two groups (p = 0.0476). h Images of the xenograft sections stained with Ki-67 and used for the quantification in (g) enzyme, MTH13, 4
Heterogeneous response to karonudib treatment in melanoma PDXes We have previously shown that TH588 and karonudib can inhibit the tumor growth of one of our PDX models[3, 4]
Summary
Cutaneous melanoma is the most aggressive form of skin cancer and is often fatal in metastatic stages[1]. (see figure on previous page) Fig. 1 A patient-derived xenograft clinical trial reveals a heterogeneous response to karonudib. Tumor biopsy from melanoma patient was serially transplanted twice in mice before being transplanted in mice treated with either karonudib or vehicle. F Kaplan–Meier graph showing the comparison of probability of progression-free survival in karonudib-treated mice (based on tumor doubling time) for the three response groups (see Materials and methods for criterion), Mantel–Cox test used for statistical analysis. G Quantification of immunohistochemical staining for the proliferation marker Ki-67 in vehicle vs karonudib-treated PDXes, Student’s t test showing statistically significant difference between the two groups (p = 0.0476). The compound has shown promising anti-tumor effect both in vitro and in vivo[4] and has initiated phase I clinical testing in cancer patients with advanced solid malignancies (NCT03036228). The exact mechanism of action of karonudib and the possible role of MTH1 in cancer is under investigation
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