Inhibition Of Isocitrate Dehydrogenase Research Articles

Dual phenotypes in recurrent astrocytoma, IDH-mutant; coexistence of IDH-mutant and IDH-wildtype components: a case report with genetic and epigenetic analysis

Mutations in the isocitrate dehydrogenase (IDH) gene are recognized as the key drivers in the oncogenesis of astrocytoma and oligodendroglioma. However, the significance of IDH mutation in tumor maintenance and malignant transformation has not been elucidated. We encountered a unique case of IDH-mutant astrocytoma that, upon malignant transformation, presented two distinct intratumoral components: one IDH-wildtype and one IDH-mutant. The IDH-wild-type component exhibited histological findings similar to those of small cell-type glioblastoma with a higher Ki-67 index than the IDH-mutant component. Despite their genetic divergence, both components exhibited similar comprehensive methylation profiles within the CpG island and were classified into methylation class of “Astrocytoma, IDH-mutant; High Grade” by the German Cancer Center (DKFZ) classifier v11.4. Phylogenetic analysis demonstrated that the IDH-wildtype component emerged as a subclonal component of the primary tumor. Detailed molecular analyses revealed that the loss of the IDH mutation was induced by the hemizygous loss of the entire arm of chromosome 2, on which IDH1 gene is located. Notably, the IDH-wild-type subclones uniquely acquired CDKN2A/B homozygous deletion and PDGFRA amplification, which is a marker of the aggressive phenotype of astrocytoma, IDH-mutant. Because these genetic abnormalities can drive oncogenic pathways, such as the PI3K/AKT/mTOR and RB signaling pathway, IDH-mutant gliomas that acquired these mutations were no longer dependent on the initial driver mutation, the IDH mutation. Molecular analysis of this unique case provides insight that in a subset of astrocytoma, IDH-mutant that acquired these genetic abnormalities, IDH mutation may not play a pivotal role in tumor growth and acquisition of these genetic abnormalities may contribute to the acquisition of resistance to IDH inhibitors.

TCA metabolism regulates DNA hypermethylation in LPS and Mycobacterium tuberculosis–induced immune tolerance

Severe and chronic infections, including pneumonia, sepsis, and tuberculosis (TB), induce long-lasting epigenetic changes that are associated with an increase in all-cause postinfectious morbidity and mortality. Oncology studies identified metabolic drivers of the epigenetic landscape, with the tricarboxylic acid (TCA) cycle acting as a central hub. It is unknown if the TCA cycle also regulates epigenetics, specifically DNA methylation, after infection-induced immune tolerance. The following studies demonstrate that lipopolysaccharide and Mycobacterium tuberculosis induce changes in DNA methylation that are mediated by the TCA cycle. Infection-induced DNA hypermethylation is mitigated by inhibitors of cellular metabolism (rapamycin, everolimus, metformin) and the TCA cycle (isocitrate dehydrogenase inhibitors). Conversely, exogenous supplementation with TCA metabolites (succinate and itaconate) induces DNA hypermethylation and immune tolerance. Finally, TB patients who received everolimus have less DNA hypermethylation demonstrating proof of concept that metabolic manipulation can mitigate epigenetic scars.

Abstract C046: Targeting wild-type IDH1 sensitizes homologous recombination proficient pancreatic cancer to PARP inhibition

Abstract Introduction: Pancreatic ductal adenocarcinoma (PDAC) is a leading cause of cancer-related mortality in the United States. While Poly (ADP-ribose) polymerase (PARP) inhibitors show promise for PDAC with Homologous Recombination Deficiency (HRD), this mutation is present in less than 10% of cases. Our research focuses on exploiting a vulnerability in the remaining 90% of HR proficient (HRP) tumors. We identified that wild-type isocitrate dehydrogenase 1 (IDH1) plays a critical role in HR repair. By inhibiting IDH1, we discovered suppression of the homologous recombination (HR) pathway, leading to compromised genomic integrity. This renders cancer cells more susceptible to PARP inhibitor therapy, offering a novel therapeutic approach for HRP PDAC. Methods:We assessed the impact of IDH1 inhibition on HR pathway activity using Western blotting to measure HR repair protein levels and HR reporter assays. The effect of IDH1 inhibition (Ivosidenib) combined with PARP inhibition (Olaparib) on in vitro growth inhibition was assessed through drug combination assays. Additionally, we investigated the molecular mechanisms underlying the synergistic effects of the drug combination. To further evaluate the therapeutic potential of IDH1 inhibition in combination with PARP inhibitors, we examined tumor growth in xenograft models of PDAC in athymic nude mice and survival studies were performed in C57BL/6J mice transplanted with orthotopic murine pancreatic cancer. Results:Wild-type IDH1 blockade induces a BRCA-like phenotype by decreasing α-ketoglutarate (αKG) levels and causing histone hypermethylation. This leads to decreased HR repair efficiency in HRP pancreatic cancer cells (MiaPaCa-2 and Panc-1), resulting in a strong synergistic effect when combined with the DNA-damaging agent Olaparib. The combination treatment significantly reduced cell survival in both short and long-term assays. Furthermore, we discovered that these compounds complemented each other in the DNA damage response, leading to increased γ-H2AX (DNA damage marker) and apoptosis. In vivo studies using murine PDAC models demonstrated that the combination of ivosidenib and olaparib synergistically enhanced anti-tumor activity compared to either single agent alone. Conclusion:These data provide novel insight into the mechanisms underlying in the context of HRP cancer susceptibility to a dual treatment approach involving an IDH1 inhibitor and a PARP inhibitor. This approach holds promise for precision medicine in pancreatic cancer treatment, although further pre- clinical studies are needed for validation and refinement. Citation Format: Mehrdad Zarei, Omid Hajihassani, Hallie J. Graor, Soubhi Tahhan, Alexander W. Loftus, Faith Nakazzi, Semmer A. Ali, Parnian Naji, Luke D. Rothermel, Jonothan R. Brody, Jordan M. Winter. Targeting wild-type IDH1 sensitizes homologous recombination proficient pancreatic cancer to PARP inhibition [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research; 2024 Sep 15-18; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl_2):Abstract nr C046.

Advances in the treatment of IDH-mutant gliomas.

Isocitrate dehydrogenase (IDH) mutation is a defining molecular driver of WHO grade 2-4 astrocytomas and oligodendrogliomas. In this article, we review the recent therapeutic approaches specifically targeting IDH-mutant gliomas and summarize ongoing clinical trials in this population. The IDH inhibitor vorasidenib recently demonstrated its efficacy after surgical resection in grade 2 IDH-mutated gliomas. Several studies in patients with IDH-mutant gliomas are currently exploring various strategies to target IDH mutations, including the use of small-molecule inhibitors, immunotherapies, peptide vaccines and agents targeting metabolic and epigenomic vulnerabilities. Mutant-IDH targeting holds significant promise in treating progressive or recurrent IDH-mutant gliomas. Recent results with IDH inhibitors will change practice and influence the existing guidelines in a near future.

Clinical and radiological response of Maffucci related enchondromas to mutant IDH1 inhibitor Ivosidenib

Ollier Disease (OD) and Maffucci syndrome (MS) is a rare bone disorder that affects the growth and development of the bones, with an estimated prevalence of 1 in 100,000 people. It is associated with somatic mosaicism of isocitrate dehydrogenase-1 (IDH1) or 2 (IDH2) pathogenic variants. Ivosidenib is indicated for the treatment of acute myeloid leukemia and locally advanced or metastatic cholangiocarcinoma and is currently investigated in low-grade glioma with a susceptible isocitrate dehydrogenase-1 (IDH1) pathogenic variant, but its effects in patients with OD or MS are unknown. We here report the first case of a patient with MS who was treated with Ivosidenib for recurrent IDH-1 mutated glioma. Besides the stabilization of the tumor size, the patient observed significant improvement in his enchondromas that became stiffer, with reduced pain, and significant modification of the mineralization of the enchondromas observed on X-rays. This first case report provides hope for the medical management of patients suffering because of OD or MS. Future clinical research is urgently needed to evaluate long-term benefit risk profile of IDH inhibitors in these rare diseases.

Molecular Targeting of the Isocitrate Dehydrogenase Pathway and the Implications for Cancer Therapy.

The advent of comprehensive genomic profiling using next-generation sequencing (NGS) has unveiled an abundance of potentially actionable genetic aberrations that have shaped our understanding of the cancer biology landscape. Isocitrate dehydrogenase (IDH) is an enzyme present in the cytosol (IDH1) and mitochondria (IDH2 and IDH3). In the mitochondrion, it catalyzes the irreversible oxidative decarboxylation of isocitrate, yielding the production of α-ketoglutarate and nicotinamide adenine dinucleotide phosphate (NADPH) as well as carbon dioxide (CO2). In the cytosol, IDH catalyzes the decarboxylation of isocitrate to α-ketoglutarate as well as the reverse reductive carboxylation of α-ketoglutarate to isocitrate. These rate-limiting steps in the tricarboxylic acid cycle, as well as the cytoplasmic response to oxidative stress, play key roles in gene regulation, cell differentiation, and tissue homeostasis. Mutations in the genes encoding IDH1 and IDH2 and, less commonly, IDH3 have been found in a variety of cancers, most commonly glioma, acute myeloid leukemia (AML), chondrosarcoma, and intrahepatic cholangiocarcinoma. In this paper, we intend to elucidate the theorized pathophysiology behind IDH isomer mutation, its implication in cancer manifestation, and discuss some of the available clinical data regarding the use of novel IDH inhibitors and their role in therapy.

The biological significance of tumor grade, age, enhancement, and extent of resection in IDH-mutant gliomas: How should they inform treatment decisions in the era of IDH inhibitors?

The 2016 and 2021 World Health Organization 2021 Classification of central nervous system tumors have resulted in a major improvement in the classification of isocitrate dehydrogenase (IDH)-mutant gliomas. With more effective treatments many patients experience prolonged survival. However, treatment guidelines are often still based on information from historical series comprising both patients with IDH wild-type and IDH-mutant tumors. They provide recommendations for radiotherapy and chemotherapy for so-called high-risk patients, usually based on residual tumor after surgery and age over 40. More up-to-date studies give a better insight into clinical, radiological, and molecular factors associated with the outcome of patients with IDH-mutant glioma. These insights should be used today for risk stratification and for treatment decisions. In many patients with IDH-mutant grades 2 and 3 glioma, if carefully monitored postponing radiotherapy and chemotherapy is safe, and will not jeopardize the overall outcome of patients. With the INDIGO trial showing patient benefit from the IDH inhibitor vorasidenib, there is a sizable population in which it seems reasonable to try this class of agents before recommending radio-chemotherapy with its delayed adverse event profile affecting quality of survival. Ongoing trials should help to further identify the patients that are benefiting from this treatment.

MDB-78. ISOCITRATE DEHYDROGENASE 1 INHIBITION PRIMES GROUP-3 MEDULLOBLASTOMAS FOR CUPROPTOSIS

Abstract BACKGROUND MYC-driven Group-3 medulloblastomas (MB) are deadly and malignant pediatric brain cancers and we sought to define actionable metabolic dependencies in these tumors. METHODS To identify uniquely upregulated genes in Group-3 MB, we performed transcriptomic analysis on two previously published medulloblastoma RNA-seq datasets. To elucidate the relationship between c-MYC/IDH1/DLAT and assess impact on tumor metabolism, we performed metabolic and transcriptional profiling of Group-3 MB cell lines that were either untreated or were subjected to shRNA-mediated knockdown of DLAT or treatment with IDH1 inhibitor. We also treated Group-3 MB cell lines containing varying levels of DLAT expression with copper ionophore elesclomol and assessed its ability to induce toxicity. Finally, we established in vivo models of Group-3 MB via orthotopic implantation to assess the effect of DLAT knockdown, IDH1 inhibition, and cuproptosis induction on tumor growth and survival outcomes. RESULTS We identified upregulation of dihydrolipoyl transacetylase (DLAT), the E2-subunit of pyruvate dehydrogenase complex (PDC) in a subset of Group-3 MB. DLAT was induced by c-MYC and targeting DLAT lowered TCA-cycle metabolism and glutathione synthesis in Group-3 MB cells. We also noted upregulation of isocitrate dehydrogenase 1 (IDH1) in Group-3 MB. Remarkably, genetic and pharmacologic suppression of IDH1 epigenetically reduced c-MYC and downstream DLAT levels. DLAT is a central regulator of cuproptosis, a copper-dependent cell death mechanism induced by the copper ionophore elesclomol. DLAT expression in Group-3 MB cells correlated with increased sensitivity to cuproptosis. Elesclomol was CNS-penetrant and suppressed tumor growth in vivo in Group-3 MB animal models. CONCLUSIONS Our data uncover an IDH1/c-MYC dependent vulnerability that regulates DLAT levels and can be targeted to kill Group-3 MB by cuproptosis.

Multidisciplinary Management of Isocitrate Dehydrogenase-Mutated Gliomas in a Contemporary Molecularly Defined Era.

Mutations in isocitrate dehydrogenase (IDH) genes, an early step in the ontogeny of lower-grade gliomas, induce global epigenetic changes characterized by a hypermethylation phenotype and are critical to tumor classification, treatment decision making, and estimation of patient prognosis. The introduction of IDH inhibitors to block the oncogenic neomorphic function of the mutated protein has resulted in new therapeutic options for these patients. To appreciate the implications of these recent IDH inhibitor results, it is important to juxtapose historical outcomes with chemoradiotherapy. Herein, we rationally evaluate recent IDH inhibitor data within historical precedents to guide contemporary decisions regarding the role of observation, maximal safe resection, adjuvant therapies, and the import of patient and tumor variables. The biological underpinnings of the IDH pathway and the mechanisms, impact, and limitations of IDH inhibitors, the actual magnitude of tumor regression and patient benefit, and emergence of resistance pathways are presented to guide future trial development. Management in the current, molecularly defined era will require careful patient selection and risk factor assessment, followed by an open dialog about the results of studies such as INDIGO, as well as mature data from legacy trials, and a discussion about risk-versus-benefit for the choice of treatment, with multidisciplinary decision making as an absolute prerequisite.

Isocitrate Dehydrogenase Inhibitors in Glioma: From Bench to Bedside.

Isocitrate dehydrogenase (IDH) mutant gliomas are a primary malignancy of the central nervous system (CNS) malignancies, most commonly affecting adults under the age of 55. Standard of care therapy for IDH-mutant gliomas involves maximal safe resection, radiotherapy, and chemotherapy. However, despite good initial responses to multimodality treatment, recurrence is virtually universal. IDH-mutant gliomas represent a life-limiting prognosis. For this reason, there is a great need for novel treatments that can prolong survival. Uniquely for IDH-mutant gliomas, the IDH mutation is the direct driver of oncogenesis through its oncometabolite 2-hydroxygluterate. Inhibition of this mutated IDH with a corresponding reduction in 2-hydroxygluterate offers an attractive treatment target. Researchers have tested several IDH inhibitors in glioma through preclinical and early clinical trials. A phase III clinical trial of an IDH1 and IDH2 inhibitor vorasidenib yielded promising results among patients with low-grade IDH-mutant gliomas who had undergone initial surgery and no radiation or chemotherapy. However, many questions remain regarding optimal use of IDH inhibitors in clinical practice. In this review, we discuss the importance of IDH mutations in oncogenesis of adult-type diffuse gliomas and current evidence supporting the use of IDH inhibitors as therapeutic agents for glioma treatment. We also examine unresolved questions and propose potential directions for future research.

Genomic medicine advances for brain tumors.

Cancer genome profiling has revealed important genetic alterations that serve as prognostic indicators and guides for treatment decisions, enabling precision medicine. The shift to molecular diagnosis of brain tumors, as reflected in the 2021 World Health Organization Classification of Tumors of the Central Nervous System, is a crucial role for treatment decision-making. This review discusses the significance and role of cancer genome profiling in precision medicine for malignant brain tumors, particularly gliomas. Furthermore, we explore the progress in cancer genome analysis, focusing on cancer gene panel testing, integration of genomic information in brain tumor classification, and hereditary tumors. Additionally, we discuss the transformative effect of genomic medicine on early detection, risk assessment, and precision medicine strategies. The tumor mutational burden in brain tumors is considered low, but the application of molecular targeted drugs, such as isocitrate dehydrogenase inhibitors, v-raf murine sarcoma viral oncogene homolog B1 inhibitors, fibroblast growth factor receptor inhibitors, neurotrophic tyrosine receptor kinase, mechanistic target of rapamycin inhibitors, and anti-programmed death receptor-1 antibody drugs are promising for glioma treatment. We also discuss the future prospects of molecular targeted drugs.

Combination therapy with novel agents for acute myeloid leukaemia: Insights into treatment of a heterogenous disease.

The treatment landscape of acute myeloid leukaemia (AML) is evolving rapidly. Venetoclax in combination with intensive chemotherapy or doublets or triplets with targeted or immune therapies is the focus of numerous ongoing trials. The development of mutation-targeted therapies has greatly enhanced the treatment armamentarium, with FLT3 inhibitors and isocitrate dehydrogenase inhibitors improving outcomes in frontline and relapsed/refractory (RR) AML, and menin inhibitors showing efficacy in RR NPM1mut and KMT2A-rearranged AML. With so many new drugs approved, the number of potential combinatorial approaches to leverage the maximal benefit of these agents has increased dramatically, while at the same time introducing clinical challenges, such as key preclinical and clinical data supporting the development of combinatorial therapy, how to optimally combine or sequence these novel agents, how to optimise dose and duration to maintain safety while enhancing efficacy, the optimal duration of therapy and the role of measurable residual disease in decision-making in both intensive and low-intensity therapy settings. In this review, we will outline the evidence leading to the approval of key agents in AML, their on-label current approvals and how they may be optimally combined in a safe and deliverable fashion to further improve outcomes in AML.

Research Progress of Isocitrate Dehydrogenase Mutation-Positive Acute Myeloid Leukemia --Review

Isocitrate dehydrogenase (IDH) is an enzymes involved in a variety of metabolic and epigenetic processes. IDH can be detected in approximately 20% of patients with acute myeloid leukemia (AML), the mutated IDH enzyme acquires new oncogenic enzyme activity and converts α-ketoglutaric acid (α-KG) to the tumor metabolite 2-hydroxyglutaric acid (2-HG), which accumulates at high levels in cells and hinders the function of αKG-dependent enzymes, including epigenetic regulators, resulting in DNA hypermethylation, abnormal gene expression, cell proliferation, and abnormal differentiation, and contributes to leukemia disease progression. IDH mutations have different effects on the prognosis of patients with AML depending on the location of the mutation and other co-occurring genomic abnormalities. This paper will review the latest research progress on the IDH positive AML gene changes, prognosis, and inhibitors.

Abstract 7125: Inhibition of IDH1 impairs homologous recombination and induces sensitivity to PARP inhibitor in pancreatic cancer

Abstract Introduction: Pancreatic ductal adenocarcinoma (PDAC) is a major cause of cancer-related deaths in the United States. While Poly (ADP-ribose) polymerase (PARP) inhibitors hold promise in treating PDAC with Homologous Recombination Deficiency (HRD). However, HRD occurs in only 10% of cases, leaving 90% with intact Homologous Recombination Proficiency (HRP). Our research highlights the key role of wild-type isocitrate dehydrogenase 1 (IDH1) in maintaining cellular function. We found that inhibiting IDH1 increases DNA damage, suppressing the DNA repair pathway crucial for genomic integrity. This makes cancer cells susceptible to PARP inhibitors, offering a new PDAC treatment approach. Methods: The effect of IDH1 inhibition (Ivosidenib) combined with PARP inhibition (Olaparib) on in vitro growth inhibition were assessed through Trypan blue and PicoGreen in drug combination assays. Additionally, we investigated the molecular mechanism underlying the synergistic effects of drug combination. To further evaluate the therapeutic potential of IDH1 inhibition in combination with PARP inhibitors, we examined tumor growth in xenograft models of PDAC in athymic nude mice. Results: Our data report that, mechanistically, IDH1 inhibition decreased expression of HR DNA repair pathway molecules, such as BRCA1 and BRCA2, and leading to decreased HR repair efficiency in pancreatic cancer cells. Short-term cell viability data demonstrated that targeting IDH1 with ivosidenib when combined with DNA-damaging agent (Olaparib) had a synergistic effect in HRP cell lines (MiaPaCa-2 and Panc-1) with a positive synergy score and Bliss score greater than 1. Additionally, we assessed long-term cell survival using colony formation assays, which yielded a dramatic reduction in cell survival for both Panc1 and MiaPaCa-2 cells when olaparib was combined with ivosidenib, as compared to single-agent controls. Consequently, this reduction increased the levels of apoptosis induced by olaparib. Furthermore, we discovered that these two compounds complemented each other in DNA damage response, leading to an increase in the DNA damage biomarker γ-H2AX. In vivo studies using xenograft models demonstrated that the combination of ivosidenib and olaparib synergistically enhanced anti-tumor activity as compared to either single-agent used alone. Conclusion: Our data provides insights into the mechanisms underlying the susceptibility of PDAC tumor growth to a dual treatment approach involving an IDH1 inhibitor and a PARP inhibitor, particularly in the context of HRP cancer. This highlights the promise of precision medicine for pancreatic cancer treatment, though further pre-clinical studies are needed for validation and refinement. Citation Format: Mehrdad Zarei, Omid Hajihassani, Hallie J. Graor, Alexander W. Loftus, Soubhi Tahhan, Faith Nakazzi, Parnian Naji, Luke D. Rothermel, Jonothan R. Brody, Jordan M. Winter. Inhibition of IDH1 impairs homologous recombination and induces sensitivity to PARP inhibitor in pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7125.

Abstract 4659: A genome-wide CRISPR screen identifies ARID1A as a potential resistance marker of IDH1 inhibitor in IDH1-mutant cholangiocarcinoma cell

Abstract Background: Isocitrate dehydrogenase 1 (IDH1) mutations have been identified in approximately 20% of intrahepatic cholangiocarcinoma cases. These predominant gain-of-function mutations at codon 132 lead to abnormal production of the oncometabolite D-2-hydroxyglutarate. Targeted pharmacological disruption of the IDH1 mutation demonstrates tumor growth inhibition in IDH1-mutated cholangiocarcinoma. However, the efficacy of an IDH1 inhibitor (AG-120) as monotherapy for IDH1-mutated cholangiocarcinoma has been proven clinically insufficient, suggesting a need for investigating predictive biomarkers. In this study, we employed a genome-wide CRISPR screen to pursue resistance mechanisms to pharmacological IDH1 inhibition. Methods: The screening utilized SNU1079 cells harboring the IDH1 R132C mutation and the Brunello genome-wide CRISPR knockout (KO) pooled library (Addgene #73178, Broad Institute GPP, 4 guides/gene). The read couns of sgRNAs were normalized to reads per million, and then log2 was transformed. The log fold change (LFC) of each sgRNA of the AG-120-treated group was determined relative to that of the DMSO-treated group. Hypergeometric distribution was used to determine statistical significance. P values per gene were calculated as the average -log10(P value) of individual sgRNAs. We validated the CRISPR screening outcomes in vitro using both IDH1R132C mutant (SNU1079) and IDH1R132S mutant (RBE) cells by WST-1 assays, clonogenic assay and competition assay. (Tsujino T et al. Nat Commun. 2023) In competition assay, GFP was constitutively expressed in ARID1A-knockout cells and cultured together with ARID1A intact cells, under treatment with 1 µM AG120 or DMSO for 21 days. Relative cell numbers of GFP-positive (ARID1A-KO) cells in comparison with GFP-negative (ARID1A intact) cells were quantified using a BD LSRFortessa Analyzer (BD Biosciences). Results: Based on a volcano plot analysis, we identified three genes (SMCHD1, ARID1A, and PGP) with LFC > 1.5. Following a recent report of frequent ARID1A alteration (20%; 84/412) in a clinical study (Boerner, et al. Hepatology. 2021), we focused our research on ARID1A (LFC = 1.531; −log10 P = 3.75). WST-1 assays and clonogenic assays as short-term (3-7 days) assays failed to validate the results of CRISPR screening; however, in competition assays under treatment with AG120, cells with ARID1A-KO exhibited significantly greater proliferation in comparison with ARID1A intact cells in two different cell lines (SNU1079, RBE). Conclusions: The results demonstrated that ARID1A disruption reduced the efficacy of the IDH1 inhibitor against IDH1-mutatedcholangiocarcinoma cells. Based on these findings, we are planning comprehensive analyses employing in vivo models and clinical data to substantiate these observations. Citation Format: Tomohiro Kondo, Osamu Kikuchi, Yafeng Wang, Yukie Nakai, Tomomi Ida, Yang Cao, Trang H. Vu, Yuki Kondo, Tomohiko Sunami, Yoshihiro Yamamoto, Tomoki Saito, Shigeki Kataoka, Atsushi Yamada, Masashi Kanai, Shinya Ohashi, Manabu Muto. A genome-wide CRISPR screen identifies ARID1A as a potential resistance marker of IDH1 inhibitor in IDH1-mutant cholangiocarcinoma cell [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4659.

Cholangiocarcinoma Insights: Established Foundations and Cutting-Edge Innovations from Dr. James Cleary’s Pioneering Research

This paper provides insights into the conventional understanding of biliary tract malignancies, with a specific focus on cholangiocarcinoma (CCA). We then delve into the groundbreaking ideas presented by Dr. James Cleary. CCA, originating from biliary tree cells, manifests diverse subtypes contingent upon anatomical localization and differentiation status. These variants exhibit discrete genetic aberrations, yielding disparate clinical phenotypes and therapeutic modalities. Intrahepatic, perihilar, and distal CCAs intricately involve distinct segments of the biliary tree, further categorized as well-differentiated, moderately differentiated, or poorly differentiated adenocarcinomas based on their histological differentiation. Understanding the etiological factors contributing to CCA development assumes paramount importance. Stratifying these factors into two groups, those unrelated to fluke infestations (e.g., viral hepatitis and fatty liver conditions) and those associated with fluke infestations (e.g., chronic liver inflammation), facilitates predictive modeling. The epidemiology of CCA exhibits global variability, with Southeast Asia notably displaying higher incidences attributed primarily to liver fluke infestations. Jaundice resulting from bile duct obstruction constitutes a prevalent clinical manifestation of CCA, alongside symptoms like malaise, weight loss, and abdominal pain. Diagnostic challenges arise due to the symptomatic overlap with other biliary disorders. Employing comprehensive liver function tests and imaging modalities such as computed tomography assumes a pivotal role in ensuring accurate diagnosis and staging. However, the definitive confirmation of CCA necessitates a biopsy. Treatment modalities, predominantly encompassing surgical resection and radiation therapy, hold curative potential, although a considerable subset of patients is deemed unresectable upon exploration. Challenges intensify, particularly in cases classified as cancer of unknown origin, underscoring the imperative for early intervention. Advancements in genomic sequencing have revolutionized precision medicine in CCA. Distinct genomic markers, including fibroblast growth factor receptor 2 (FGFR2) alterations and isocitrate dehydrogenase 1 (IDH1) mutations, have emerged as promising therapeutic targets. FGFR2 alterations, encompassing mutations and rearrangements, play pivotal roles in oncogenesis, with FGFR inhibitors demonstrating promise despite identified resistance mechanisms. Similarly, IDH1 inhibitors face challenges with resistance, despite encouraging early clinical trial results, prompting exploration of novel irreversible inhibitors. Dr. James Cleary’s illuminating discourse underscores the significance of diverse FGFR2 alterations and the potential of IDH1 inhibition in reshaping the treatment landscape for CCA. These findings unveil critical avenues for targeted therapeutic interventions, emphasizing the critical need for ongoing research to optimize outcomes in this challenging cancer subtype, incorporating innovative insights from Dr. Cleary.

IDH1 and IDH2 Gene Mutations in Omani Patients with Acute Myeloid Leukemia: Prognostic Significance and Clinic-pathologic Features.

We sought to define the prevalence of isocitrate dehydrogenase (IDH) mutations, evaluate the clinicopathologic impact of IDH mutations, assess the effect of IDH mutations on the response to the currently offered treatment for acute myeloid leukemia (AML) cases, and determine the impact of other common concurrent mutations with IDH. A single-center retrospective cohort study was conducted at Sultan Qaboos University Hospital (SQUH) from October 2009 to October 2019. We included all Omani patients (pediatric and adult) treated at SQUH with the standard therapy, for whom DNA extraction was performed at diagnosis. The target mutations in both IDH1 and IDH2 genes were screened using the direct polymerase chain reaction product sequencing method. Statistical analysis was conducted using SPSS software. Survival differences were estimated using the log-rank test. Continuous variables were presented as median (IQRs), while categorical variables were presented as frequency. A total of 61 patients treated, for whom DNA extraction was performed at diagnosis were evaluated. The median age was 40 (range = 25.5-65.5). The prevalence of IDH1 R132, IDH2 R140, and IDH2 R172 mutations among the study group was 6.6%, 3.3%, and 1.6%, respectively. Clinicopathologic characteristics associated with IDH mutations at diagnosis included older age, lower white blood cell count, higher median platelet counts, normal karyotype AML, and cytogenetics intermediate-risk group. The overall survival (OS) in patients harboring IDH mutations was poor, with a median OS of nine months. This analysis confirms that the response rate and OS for both IDH-mutated and IDH wild-type AML patients were comparable. This will provide contemporary data to be used for comparison with the results of novel investigational (e.g., selective IDH inhibitor) strategies. The current study results were consistent with the other international studies of IDH mutations in AML and demonstrate the poor prognosis associated with IDH mutations. Clinicopathologic features associated with IDH mutations included older age, lower white blood cell count, higher median platelet counts, normal karyotype AML, and cytogenetics intermediate-risk group.

Improved prognostic stratification of patients with isocitrate dehydrogenase-mutant astrocytoma

Prognostic factors and standards of care for astrocytoma, isocitrate dehydrogenase (IDH)-mutant, CNS WHO grade 4, remain poorly defined. Here we sought to explore disease characteristics, prognostic markers, and outcome in patients with this newly defined tumor type. We determined molecular biomarkers and assembled clinical and outcome data in patients with IDH-mutant astrocytomas confirmed by central pathology review. Patients were identified in the German Glioma Network cohort study; additional cohorts of patients with CNS WHO grade 4 tumors were identified retrospectively at two sites. In total, 258 patients with IDH-mutant astrocytomas (114 CNS WHO grade 2, 73 CNS WHO grade 3, 71 CNS WHO grade 4) were studied. The median age at diagnosis was similar for all grades. Karnofsky performance status at diagnosis inversely correlated with CNS WHO grade (p < 0.001). Despite more intensive treatment upfront with higher grade, CNS WHO grade was strongly prognostic: median overall survival was not reached for grade 2 (median follow-up 10.4 years), 8.1 years (95% CI 5.4–10.8) for grade 3, and 4.7 years (95% CI 3.4–6.0) for grade 4. Among patients with CNS WHO grade 4 astrocytoma, median overall survival was 5.5 years (95% CI 4.3–6.7) without (n = 58) versus 1.8 years (95% CI 0–4.1) with (n = 12) homozygous CDKN2A deletion. Lower levels of global DNA methylation as detected by LINE-1 methylation analysis were strongly associated with CNS WHO grade 4 (p < 0.001) and poor outcome. MGMT promoter methylation status was not prognostic for overall survival. Histomolecular stratification based on CNS WHO grade, LINE-1 methylation level, and CDKN2A status revealed four subgroups of patients with significantly different outcomes. In conclusion, CNS WHO grade, global DNA methylation status, and CDKN2A homozygous deletion are prognostic in patients with IDH-mutant astrocytoma. Combination of these parameters allows for improved prediction of outcome. These data aid in designing upcoming trials using IDH inhibitors.

Neuro-oncology Treatment Strategies for Primary Glial Tumors.

Primary brain tumors underwent reclassification in the 2021 World Health Organization update, relying on molecular findings (especially isocitrate dehydrogenase mutations and chromosomal changes in 1p, 19q, gain of chromosome 7 and loss of chromosome 10). Newer entities have also been described including histone 3 mutant midline gliomas. These updated pathologic classifications improve prognostication and reliable diagnosis, but may confuse interpretation of prior clinical trials and require reclassification of patients diagnosed in the past. For patients over seventy, multiple studies have now confirmed the utility of shorter courses of radiation, and the risk of post-operative delirium. Ongoing studies are comparing proton to photon radiation. Long term follow up of prior clinical trials have confirmed the roles and length of chemotherapy (mainly temozolomide) in different tumors, as well as the wearable novottf device. New oral isocitrate dehydrogenase inhibitors have also shown efficacy in clinical trials.

Despite High Rates of Remission, Treatment of IDH-Mutant AML with Hypomethylating Agents and Venetoclax Is Associated with Frequent Treatment Delays, Modifications, and Transfusions

Introduction: 25-30% of adult patients with AML have mutations in the isocitrate dehydrogenase (IDH) genes, IDH1 or IDH2. Hypomethylating agents (HMA) and venetoclax (Ven) is a widely used combination in induction-ineligible patients with IDH mutations. A subset analysis of VIALE-A data showed composite complete remission or complete remission with incomplete hematologic recovery (CR/CRi) rate of 79% and median overall survival (mOS) of 24.5 months with frontline azacitidine and Ven. IDH1-mutant and IDH2-mutant patients had CR/CRi rates of 66.7% and 86.0%, respectively. IDH1-mutant patients had mOS of 15.2 months and IDH2-mutant patients did not reach mOS. We report a single-center retrospective analysis of HMA/Ven in patients with IDH mutations. Methods: This single-center retrospective study examined all patients with IDH mutations who received HMA/Ven from January 1, 2018 to June 30, 2023 at Memorial Sloan Kettering Cancer Center and summarizes their characteristics and outcomes. Demographics, adverse events, treatment course, and laboratory and transfusion data were retrospectively reviewed with institutional IRB approval. Results: Ninety-four patients, 50 with newly diagnosed (ND) AML and 44 with relapsed/refractory (R/R) AML, were identified (Table 1). 32% (n=16) of ND patients and 41% (n=18) of R/R patients had IDH1 mutations and 68% (n=34) of ND patients and 59% (n=26) of R/R patients had IDH2 mutations. With median follow-up of 21.9 months, mOS was 29.2 months (95% CI 17.9, NA) for ND patients and 17.1 months (95% CI 12.1, 34.2) for R/R patients (Figure 1). The CR/CRi rate was 76% (n=38; 30% CR, n=15; 46% CRi, n=23) for ND patients and 52% (n=23; 32% CR, n=14; 20% CRi, n=9) for R/R patients. Patients received median of 3 cycles of HMA/Ven (range 1, 22) and experienced frequent treatment modifications and delays. Of 356 total cycles, 62% (n=218) were modified to have fewer than 28 days of venetoclax, 7 days of azacitidine, or 5 days of decitabine. In addition, 296 cycle holds or delays of at least one week occurred. 66.2% (n=196) of holds or delays were due to cytopenia and 11.5% (n=34) were due to infection. 77% (n=72) of patients had Common Terminology Criteria for Adverse Events (CTCAE) grade 3 pancytopenia and 47% (n=44) had febrile neutropenia. Through 356 cycles spanning 21,386 patient-days, 5,651 complete blood counts (CBCs, mean 15.9 per cycle), 986 red blood cell transfusions, (RBC, mean 2.8 per cycle) and 1,018 platelet transfusions (PLT, mean 2.9 per cycle) were recorded at our center. Additional CBCs or transfusions performed externally were not captured. After CR/CRi, dose adjustments, cycle holds or delays, and cytopenias remained frequent. The 63 patients that achieved CR/CRi underwent 198 cycles, 71% (n=141) of which were modified as above. There were 209 holds or delays (65%, n=136 for cytopenias, 10%, n=21 for infection). Median time between cycles was 7 weeks. Cycles given after CR/CRi frequently resulted in grade 3 cytopenias by CTCAE (neutropenia: 82%, n=163; anemia: 15%, n=29; thrombocytopenia: 37%, n=74). Through 198 cycles spanning 13,463 patient-days, 2,426 CBCs (mean 12.3 per cycle), 141 RBC transfusions, (mean 0.7 per cycle) and 236 PLT transfusions (mean 1.2 per cycle) were performed. At last follow-up, 28% (n=14) of ND AML patients continued HMA/Ven, whereas 28% (n=14) had proceeded to allogeneic stem cell transplantation (alloSCT), 28% (n=14) were relapsed or refractory to HMA/Ven, and 12% (n=6) were deceased. For R/R AML patients, 20% (n=9) continued HMA/Ven but 27% (n=12) had proceeded to alloSCT, 34% (n=15) were relapsed or refractory, and 14% (n=6) were deceased. Of the 68 patients who were no longer receiving HMA/Ven at end of follow-up, only 23.5% (n=16) of patients received an IDH-inhibitor in their next line of therapy, the rest primarily transitioning to alloSCT (38.2%, n=26), chemotherapy (8.8%, n=6), or supportive measures (20.6%, n=14). Conclusion: In a single-center retrospective setting, HMA/Ven is efficacious in achieving CR/CRi in ND and R/R IDH-mutant AML. However, its use, even in CR/CRi, is associated with significant cytopenias and infections that necessitate indefinite and frequent treatment modification, laboratory utilization, and transfusions. A strategy that incorporates HMA/Ven followed by non-myelosuppressive targeted therapy with IDH inhibition as maintenance should be explored to minimize these toxicities.