Targeting therapeutic vulnerabilities with PARP inhibition and radiation in IDH-mutant gliomas and cholangiocarcinomas

Yuxiang Wang, Aaron T Wild, Sevin Turcan, Wei H Wu, Carlie Sigel, David S Klimstra, Xiaoxiao Ma, Yongxing Gong, Eric C Holland, Jason T Huse, Timothy A Chan, Yuxiang Wang, Aaron T Wild, Sevin Turcan, Wei H Wu, Carlie Sigel, David S Klimstra, Xiaoxiao Ma, Yongxing Gong, Eric C Holland, Jason T Huse, Timothy A Chan

Abstract

Mutations in isocitrate dehydrogenase (IDH) genes occur in multiple cancer types, lead to global changes in the epigenome, and drive tumorigenesis. Yet, effective strategies targeting solid tumors harboring IDH mutations remain elusive. Here, we demonstrate that IDH-mutant gliomas and cholangiocarcinomas display elevated DNA damage. Using multiple in vitro and preclinical animal models of glioma and cholangiocarcinoma, we developed treatment strategies that use a synthetic lethality approach targeting the reduced DNA damage repair conferred by mutant IDH using poly(adenosine 5'-diphosphate) ribose polymerase inhibitors (PARPis). The therapeutic effects are markedly enhanced by cotreatment with concurrent, localized radiation therapy. PARPi-buttressed multimodality therapies may represent a readily applicable approach that is selective for IDH-mutant tumor cells and has potential to improve outcomes in multiple cancers.

Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC).

Figures

Fig. 1. Mutant IDH1 induces DNA damage…
Fig. 1. Mutant IDH1 induces DNA damage response and radiosensitizes IHA to PARP inhibition.
(A) Quantification of γ-H2AX positivity based on the number of foci. Fifty nuclei were quantified under each condition. (B) Western blots of phospho-KAP1 (p-KAP1) and the loading control (β-actin). Samples were loaded in duplicates. (C) Relative intensity of each condition in (B) was quantified and plotted. (D) Immunostaining of γ-H2AX in vehicle (veh)–, olaparib (ola)–, IR-, or IR + olaparib–treated IHA cells expressing either EV or IDH1mut. DAPI, 4′,6-diamidino-2-phenylindole. Scale bar,10 μm. (E) Quantification of (D), performed by measuring the percentage of nuclei with more than 10 foci (left) (the numbers at bottom of bar graphs are correspondent to numbers in the panel) or average foci number of 50 nuclei (right). (F) Neutral Comet assays determining DNA breaks in IHA-EV and IHA-IDH1mut. Scale bars, 200 μm. (G) The length of comet tails was measured and represented on the plot. (H) Apoptotic activities of IHA after radiation and/or olaparib treatment were measured for annexin V and propidium iodide (PI) positivity. (I) The PI+ and annexin V+ double positive populations were plotted on the bar graph. (J) IHA, expressing EV or IDH1mut, was subjected to soft agar colony formation assay, treated with four conditions: vehicle, veliparib (20 μM), IR [1 to 4 grays (Gy)], or IR + veliparib in combination. Plot showed radiosensitization by veliparib in IDH1mut IHA versus EV. Where applicable, error bars represent the SEM. P values were determined by Student’s t test and represented using **P < 0.01, ***P < 0.001, and ****P < 0.0001. n.s., not significant.
Fig. 2. IDH1-mutant cholangiocarcinoma and sensitivity to…
Fig. 2. IDH1-mutant cholangiocarcinoma and sensitivity to PARP inhibition.
(A) Confirmation of IDH1mut expression in HUCCT1 cholangiocarcinoma cell line. Lysates from HUCCT1-EV or HUCCT1-IDH1mut were subjected to Western blots determining expression of IDH1 R132H. Loading control is performed with anti-vinculin. (B) Immunostaining of γ-H2AX in HUCCT1-EV and HUCCT1-IDH1mut after IR (4 Gy) or olaparib (4 μM), or both, showing synergy specifically in HUCCT1-IDH1mut. Scale bar, 10 μm. (C) The average number of γ-H2AX foci in (B) were quantified and shown as means ± SEM. (D) Neutral Comet assays showed different levels of DNA damage between the indicated treatments. Scale bars, 200 μm. (E) The Comet tail moment lengths were individually quantified and compared. (F) Representative results of colony formation assay with HUCCT1-EV or HUCCT1-IDH1mut treated with increasing doses of IR (2, 4, and 6 Gy), with or without olaparib (4 μM). (G) The colonies of all conditions were quantified and represented on a survival plot showing synergestic effect of olaparib and IR specifically in HUCCT1-IDH1mut cells. Photo credit: Yuxiang Wang, Memorial Sloan Kettering Cancer Center (MSKCC). (H) Immunostaining of γ-H2AX in IDHwt (HUCCT1) and IDH1mut (SNU-1079) cell lines, treated with IR (4 Gy) + olaparib (4 μM). wt, wild-type. (I) Results from clonogenic assays with IDHwt (HUCCT1) and IDH1mut (SNU-1079) cholangiocarcinoma cell lines. Panel shows representative results when cells were treated with IR (4 Gy) + olaparib 4 μM. Photo credit: Yuxiang Wang, MSKCC. (J) The colonies in IR (4 Gy) + olaparib (4 μM) were quantified and divided by the IR-alone control. P values were determined by Student’s t test and represented using **P < 0.01, ***P < 0.001, and ****P < 0.0001.
Fig. 3. Human IDH-mutant glioma and cholangiocarcinoma…
Fig. 3. Human IDH-mutant glioma and cholangiocarcinoma tumors display elevated DDR levels.
(A) Frozen glioma specimens were collected during routine surgeries at MSKCC (see also the “Human pathology” section under Materials and Methods). Four grade III oligodendroglioma (top) and six grade III astrocytoma (bottom) samples were stained for γ-H2AX positivity, and representative images are shown in the panels. (B) H-scores of five 20× fields of each sample were calculated and reported on the bar graphs as means ± SEM. Top: Comparison of H-scores of the oligodendroglioma sample pair. Bottom: Comparison of H-scores of the astrocytoma sample pair. ****P < 0.0001, determined by Student’s t test. (C) Sections from six cholangiocarcinoma specimens (three IDHwt and three IDHmut) were stained for γ-H2AX positivity, and representative images are shown in the panels. (D) Top: For top panels of (C), H-scores of five 20× fields of each sample were calculated and represented on the bar graphs as means ± SEM. Bottom: Comparison of H-scores of the bottom panels in (C). ****P < 0.0001, determined by Student’s t test.
Fig. 4. Treatment with PARPi and RT…
Fig. 4. Treatment with PARPi and RT significantly improved survival of mice with IDH-mutant neurosphere-derived intracranial tumors.
(A) Work flow of treatments. Mice received GSC implantation. All mice received weekly BLI scans, and the results were recorded. All mice with established tumors (over the defined threshold) were equally distributed to vehicle, veliparib (veli), RT, or RT + veliparib arms. TX, treatment; PATH, pathologic analysis. (B) Kaplan-Meier analysis of mice bearing TS543 GSC (IDHwt) cells, starting from the day they entered trials. P values were determined by log-rank (Mantel-Cox) test. (C) Kaplan-Meier analysis of mice bearing TS603 GSC (IDH1mut), starting from the day they entered trials. (D) Representative BLI scans of paired mice receiving RT or RT + veliparib. Top: BLI scans at day 0. Bottom: Scans at day 7. (E) Responses based on BLI reads for RT + veliparib–treated (left) (n = 16) and RT-treated (right) (n = 13) mice. Dashed line indicates a 90% reduction in tumor BLI signal. (F) Pie graphs showing the percentage of any reduction (top), >90% reduction (middle), or increase of >800% (bottom) in BLI. Statistics were performed with chi-square test, and the P values are presented. D, day.
Fig. 5. PARPi + RT significantly improves…
Fig. 5. PARPi + RT significantly improves survival of RCAS-TVA mice bearing mutant IDH1 gliomas.
(A) Mice receiving intracranial injection of RCAS virus-producing cells carrying platelet-derived growth factor A (PDGFA), shTP53, and either IDHwt or IDHmut expression cassettes were maintained for 5 weeks before their initial MRI scans. After MRI, mice were equally distributed into four-arm treatment groups based on tumor volume. (B) Kaplan-Meier analysis of mice bearing IDHwt gliomas, starting from the day they entered trials. P values were determined by log-rank (Mantel-Cox) test. (C) Kaplan-Meier analysis of mice bearing IDH1mut gliomas. (D) Representative images of MRI scans from (C) at days 0, 7, and 21, showing overall effect of treatments. (E) Kaplan-Meier analysis of mice bearing IDH1mut gliomas, receiving BGB PARPi + RT treatments. (F) Representative images of MRI scans from (E) at days 0, 7, and 21, showing overall effect of treatments.
Fig. 6. PARPi + RT significantly improved…
Fig. 6. PARPi + RT significantly improved survival of nude mice bearing IDH1-mutant cholangiocarcinoma xenografts.
(A) Mice received subcutaneous injection of HUCCT1 cells expressing EV or IDH1mut. Three weeks after injection, the hind flank tumors were measured and equally distributed to four-arm treatment groups when tumors exceeded the defined threshold of 100 mm3. The tumor sizes were measured twice a week. (B) Tumor growth of HUCCT1-EV xenografts with the indicated treatments. P values were calculated using two-way ANOVA. (C) Kaplan-Meier analysis of HUCCT1-EV xenografts with the indicated treatments. P values were determined by log-rank (Mantel-Cox) test. (D) Tumor growth of HUCCT1-IDH1mut xenografts with the indicated treatments. (E) Kaplan-Meier analysis of HUCCT1-IDH1mut xenografts. (F) Mice were sacrificed at day 6, and tumor tissues were subjected to pathological analyses. Hematoxylin and eosin (H&E) staining was performed. (G) The mitotic cell numbers per 400× field were counted, and means ± SEM was shown on the bar graphs. For each condition, 10 400× fields were quantified. *P < 0.05 and **P < 0.01. P values were determined by Student’s t test.

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