RESUMO
Hereditary leiomyomatosis and renal cell carcinoma (HLRCC) is caused by loss of function mutations in fumarate hydratase (FH) and results in an aggressive subtype of renal cell carcinoma with limited treatment options. Loss of FH leads to accumulation of fumarate, an oncometabolite that disrupts multiple cellular processes and drives tumor progression. High levels of fumarate inhibit alpha ketoglutarate-dependent dioxygenases, including the ten eleven translocation (TET) enzymes and can lead to global DNA hypermethylation. Here, we report patterns of hypermethylation in FH-mutant cell lines and tumor samples are associated with silencing of nicotinate phosphoribosyl transferase (NAPRT), a rate-limiting enzyme in the Preiss-Handler pathway of NAD+ biosynthesis in a subset of HLRCC cases. NAPRT is hypermethylated at a CpG island in the promoter in cell line models and patient samples, resulting in loss of NAPRT expression. We find that FH-deficient RCC models with loss of NAPRT expression, as well as other oncometabolite-producing cancer models that silence NAPRT, are extremely sensitive to nicotinamide phosphoribosyl transferase inhibitors (NAMPTis). NAPRT silencing was also associated with synergistic tumor cell killing with poly(ADP)-ribose polymerase inhibitors (PARPis) and NAMPTis, which was associated with effects on PAR-mediated DNA repair. Overall, our findings indicate that NAPRT-silencing can be targeted in oncometabolite-producing cancers and elucidates how oncometabolite associated hypermethylation can impact diverse cellular processes and leads to therapeutically relevant vulnerabilities in cancer cells. Implications: NAPRT is a novel biomarker for targeting NAD+ metabolism in FH-deficient HLRCCs with NAMPTis alone and targeting DNA repair processes with the combination of NAMPTis and PARPis.
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The treatment of primary central nervous system tumors is challenging due to the blood-brain barrier and complex mutational profiles, which is associated with low survival rates. However, recent studies have identified common mutations in gliomas [isocitrate dehydrogenase (IDH)-wild-type and mutant, WHO grades II-IV; with grade IV tumors referred to as glioblastomas (GBM)]. These mutations drive epigenetic changes, leading to promoter methylation at the nicotinic acid phosphoribosyl transferase (NAPRT) gene locus, which encodes an enzyme involved in generating NAD+. Importantly, NAPRT silencing introduces a therapeutic vulnerability to inhibitors targeting another NAD+ biogenesis enzyme, nicotinamide phosphoribosyl transferase (NAMPT), rationalizing a treatment for these malignancies. Multiple systemically administered NAMPT inhibitors (NAMPTi) have been developed and tested in clinical trials, but dose-limiting toxicities-including bone marrow suppression and retinal toxicity-have limited their efficacy. Here, we report a novel approach for the treatment of NAPRT-silenced GBMs using nanoparticle (NP)-encapsulated NAMPTis administered by convection-enhanced delivery (CED). We demonstrate that GMX1778 (a NAMPTi) can be formulated in degradable polymer NPs with retention of potency for NAMPT inhibition and anticancer activity in vitro, plus sustained drug release in vitro and in vivo. Direct injection of these drugs via CED into the brain is associated with reduced retinal toxicity compared with systemic administration. Finally, we show that CED of NP-encapsulated GMX1778 to NAPRT-silenced intracranial GBM xenografts in mice exhibit significant tumor growth delay and extends survival. These data support an approach to treat gliomas harboring defects in NAD+ metabolism using CED of NP-encapsulated NAMPTis to greatly improve the therapeutic index and treatment efficacy for this class of drugs.
Assuntos
Glioma , Nanopartículas , Nicotinamida Fosforribosiltransferase , Nicotinamida Fosforribosiltransferase/antagonistas & inibidores , Humanos , Animais , Camundongos , Nanopartículas/química , Glioma/tratamento farmacológico , Glioma/patologia , Citocinas/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto , Linhagem Celular Tumoral , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/patologiaRESUMO
Aberrant DNA repair is a hallmark of cancer, and many tumors display reduced DNA repair capacities that sensitize them to genotoxins. Here, we demonstrate that the differential DNA repair capacities of healthy and transformed tissue may be exploited to obtain highly selective chemotherapies. We show that the novel N3-(2-fluoroethyl)imidazotetrazine "KL-50" is a selective toxin toward tumors that lack the DNA repair protein O6-methylguanine-DNA-methyltransferase (MGMT), which reverses the formation of O6-alkylguanine lesions. We establish that KL-50 generates DNA interstrand cross-links (ICLs) by a multistep process comprising DNA alkylation to generate an O6-(2-fluoroethyl)guanine (O6FEtG) lesion, slow unimolecular displacement of fluoride to form an N1,O6-ethanoguanine (N1,O6EtG) intermediate, and ring-opening by the adjacent cytidine. The slow rate of N1,O6EtG formation allows healthy cells expressing MGMT to reverse the initial O6FEtG lesion before it evolves to N1,O6EtG, thereby suppressing the formation of toxic DNA-MGMT cross-links and reducing the amount of DNA ICLs generated in healthy cells. In contrast, O6-(2-chloroethyl)guanine lesions produced by agents such as lomustine and the N3-(2-chloroethyl)imidazotetrazine mitozolomide rapidly evolve to N1,O6EtG, resulting in the formation of DNA-MGMT cross-links and DNA ICLs in healthy tissue. These studies suggest that careful consideration of the rates of chemical DNA modification and biochemical DNA repair may lead to the identification of other tumor-specific genotoxic agents.
Assuntos
Neoplasias Encefálicas , Resistencia a Medicamentos Antineoplásicos , Humanos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/patologia , Antineoplásicos/farmacologia , Antineoplásicos/química , Antineoplásicos/síntese química , Antineoplásicos/uso terapêutico , Linhagem Celular Tumoral , Reparo do DNA/efeitos dos fármacos , O(6)-Metilguanina-DNA Metiltransferase/metabolismo , O(6)-Metilguanina-DNA Metiltransferase/antagonistas & inibidores , Imidazóis/química , Imidazóis/farmacologia , Imidazóis/uso terapêuticoRESUMO
DNA damage response (DDR) mechanisms are critical to maintenance of overall genomic stability, and their dysfunction can contribute to oncogenesis. Significant advances in our understanding of DDR pathways have raised the possibility of developing therapies that exploit these processes. In this expert-driven consensus review, we examine mechanisms of response to DNA damage, progress in development of DDR inhibitors in IDH-wild-type glioblastoma and IDH-mutant gliomas, and other important considerations such as biomarker development, preclinical models, combination therapies, mechanisms of resistance and clinical trial design considerations.
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Neoplasias Encefálicas , Dano ao DNA , Humanos , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/terapia , Neoplasias Encefálicas/patologia , Pesquisa Translacional Biomédica , Animais , Reparo do DNA , Glioma/genética , Glioma/terapia , Glioma/patologia , Consenso , MutaçãoRESUMO
The morbidity associated with pediatric medulloblastoma, in particular in patients who develop leptomeningeal metastases, remains high in the absence of effective therapies. Administration of substances directly into the cerebrospinal fluid (CSF) is one approach to circumvent the blood-brain barrier and focus delivery of drugs to the site of tumor. However, high rates of CSF turnover prevent adequate drug accumulation and lead to rapid systemic clearance and toxicity. Here, we show that PLA-HPG nanoparticles, made with a single-emulsion, solvent evaporation process, can encapsulate talazoparib, a PARP inhibitor (BMN-673). These degradable polymer nanoparticles improve the therapeutic index when delivered intrathecally and lead to sustained drug retention in the tumor as measured with PET imaging and fluorescence microscopy. We demonstrate that administration of these particles into the CSF, alone or in combination with systemically administered temozolomide, is a highly effective therapy for tumor regression and prevention of leptomeningeal spread in xenograft mouse models of medulloblastoma. These results provide a rationale for harnessing nanoparticles for the delivery of drugs limited by brain penetration and therapeutic index and demonstrate important advantages in tolerability and efficacy for encapsulated drugs delivered locoregionally.
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Antineoplásicos , Neoplasias Cerebelares , Meduloblastoma , Nanopartículas , Criança , Humanos , Camundongos , Animais , Inibidores de Poli(ADP-Ribose) Polimerases/farmacologia , Inibidores de Poli(ADP-Ribose) Polimerases/uso terapêutico , Meduloblastoma/tratamento farmacológico , Antineoplásicos/uso terapêutico , Neoplasias Cerebelares/tratamento farmacológico , Líquido CefalorraquidianoRESUMO
Purpose: O6-methylguanine DNA methyltransferase (MGMT)-silenced tumors reveal sensitivity to temozolomide (TMZ), which may be enhanced by PARP inhibitors. Approximately 40% of colorectal cancer has MGMT silencing and we aimed to measure antitumoral and immunomodulatory effects from TMZ and olaparib in colorectal cancer. Experimental Design: Patients with advanced colorectal cancer were screened for MGMT promoter hypermethylation using methylation-specific PCR of archival tumor. Eligible patients received TMZ 75 mg/m2 days 1-7 with olaparib 150 mg twice daily every 21 days. Pretreatment tumor biopsies were collected for whole-exome sequencing (WES), and multiplex quantitative immunofluorescence (QIF) of MGMT protein expression and immune markers. Results: MGMT promoter hypermethylation was detected in 18/51 (35%) patients, 9 received study treatment with no objective responses, 5/9 had stable disease (SD) and 4/9 had progressive disease as best response. Three patients had clinical benefit: carcinoembryonic antigen reduction, radiographic tumor regression, and prolonged SD. MGMT expression by multiplex QIF revealed prominent tumor MGMT protein from 6/9 patients without benefit, while MGMT protein was lower in 3/9 with benefit. Moreover, benefitting patients had higher baseline CD8+ tumor-infiltrating lymphocytes. WES revealed 8/9 patients with MAP kinase variants (7 KRAS and 1 ERBB2). Flow cytometry identified peripheral expansion of effector T cells. Conclusions: Our results indicate discordance between MGMT promoter hypermethylation and MGMT protein expression. Antitumor activity seen in patients with low MGMT protein expression, supports MGMT protein as a predictor of alkylator sensitivity. Increased CD8+ TILs and peripheral activated T cells, suggest a role for immunostimulatory combinations. Significance: TMZ and PARP inhibitors synergize in vitro and in vivo in tumors with MGMT silencing. Up to 40% of colorectal cancer is MGMT promoter hypermethylated, and we investigated whether TMZ and olaparib are effective in this population. We also measured MGMT by QIF and observed efficacy only in patients with low MGMT, suggesting quantitative MGMT biomarkers more accurately predict benefit to alkylator combinations.
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Neoplasias do Colo , Neoplasias Colorretais , Neoplasias Retais , Humanos , Temozolomida/farmacologia , Inibidores de Poli(ADP-Ribose) Polimerases/farmacologia , Reparo do DNA , O(6)-Metilguanina-DNA Metiltransferase , Neoplasias Colorretais/tratamento farmacológico , AlquilantesRESUMO
Purpose: Isocitrate dehydrogenase (IDH) 1 and IDH2 mutations (IDH1/2mt) are frequent in glioma. Preclinical studies suggest IDH1/2mts confer "BRCAness" phenotype, a vulnerability that can be targeted through PARP inhibition. To test this hypothesis, we conducted a multicenter study of olaparib monotherapy in patients with IDH1/2mt gliomas. Methods: Patients with recurrent, contrast-enhancing IDH1/2mt gliomas were enrolled in a two-step phase II trial; the primary endpoint was overall response rate per Response Assessment in Neuro-Oncology (RANO) criteria. Olaparib 300 mg orally twice daily was given. Results: A total of 15 evaluable patients were enrolled. Histology was astrocytoma (N = 12) and oligodendroglioma (N = 3). Most toxicities were grade 1 or 2. Best response was stable disease (SD) in 9 (60%) patients. Median progression-free survival (PFS) was 3.63 months and median overall survival was 20.7 months. For patients with SD, median PFS was 5.53 months; 4 patients had SD for >6 months. Among patients with best response progressive disease (N = 6), 5 had grade 4 tumor and 4 had known CDKN2A alteration. PFS was 5.23 months for grades 2 or 3 tumors (N = 10) versus 1.8 months for grade 4 (N = 5; P = 0.0013). Conclusion: The study did not meet the prespecified response-based activity threshold for moving to step 2. However, prolonged SD was observed in patients with grades 2 and 3 histologies, suggesting olaparib monotherapy could be of clinical benefit in select populations. Grade 4 tumors per 2021 World Health Organization classification defined by histology or CDKN2A alteration derived no benefit from this drug, highlighting the usefulness of this classification for future patient stratification and trial design. Significance: A single-arm phase II trial of olaparib in IDH-mutant glioma demonstrated clinically significant prolonged SD for select patients with grade 2/3 disease, suggesting potential benefit of olaparib in IDH-mutant gliomas.
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Antineoplásicos , Neoplasias Encefálicas , Glioma , Humanos , Inibidores de Poli(ADP-Ribose) Polimerases/efeitos adversos , Neoplasias Encefálicas/tratamento farmacológico , Isocitrato Desidrogenase/genética , Recidiva Local de Neoplasia/tratamento farmacológico , Glioma/tratamento farmacológico , Antineoplásicos/efeitos adversosRESUMO
Glioblastoma (GBM) is one of the most lethal malignancies with poor survival and high recurrence rates. Here, we aimed to simultaneously target oncomiRs 10b and 21, reported to drive GBM progression and invasiveness. We designed short (8-mer) γ-modified peptide nucleic acids (sγPNAs), targeting the seed region of oncomiRs 10b and 21. We entrapped these anti-miR sγPNAs in nanoparticles (NPs) formed from a block copolymer of poly(lactic acid) and hyperbranched polyglycerol (PLA-HPG). The surface of the NPs was functionalized with aldehydes to produce bioadhesive NPs (BNPs) with superior transfection efficiency and tropism for tumor cells. When combined with temozolomide, sγPNA BNPs administered via convection-enhanced delivery (CED) markedly increased the survival (>120 days) of two orthotopic (intracranial) mouse models of GBM. Hence, we established that BNPs loaded with anti-seed sγPNAs targeting multiple oncomiRs are a promising approach to improve the treatment of GBM, with a potential to personalize treatment based on tumor-specific oncomiRs.
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Neoplasias Encefálicas , Glioblastoma , Nanopartículas , Ácidos Nucleicos Peptídicos , Camundongos , Animais , Ácidos Nucleicos Peptídicos/farmacologia , Encéfalo/patologia , Glioblastoma/patologia , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/patologia , Temozolomida , Linhagem Celular TumoralRESUMO
OBJECTIVE: Because of the aggressive nature of glioblastoma, patients with unresected disease are encouraged to begin radiotherapy within approximately 1 month after craniotomy. The aim of this study was to investigate the potential association between time interval from biopsy to radiotherapy with overall survival in patients with unresected glioblastoma. METHODS: Patients with unresected glioblastoma diagnosed between 2010 and 2014 who received adjuvant radiotherapy and concurrent chemotherapy were identified in the National Cancer Database. Demographic and clinical data were compared using chi-square and Wilcoxon rank-sum tests. Survival was analyzed using the Kaplan-Meier method and Cox proportional hazards regression modeling. RESULTS: Among 3456 patients with unresected glioblastoma, initiation of radiotherapy within 3 weeks of biopsy was associated with a higher hazard of death compared with later initiation of radiotherapy. After excluding patients who received radiotherapy within 3 weeks of biopsy to minimize the effects of confounders associated with short time intervals from biopsy to radiotherapy, the median interval from biopsy to radiotherapy was 32 days (IQR 27-39 days). Overall, 1782 (66.82%) patients started radiotherapy within 5 weeks of biopsy, and 885 (33.18%) patients started radiotherapy beyond 5 weeks of biopsy. On multivariable analysis, there was no significant difference in overall survival between these two groups (HR 0.96, 95% CI 0.88-1.50; p = 0.374). CONCLUSIONS: In patients with unresected glioblastoma, a longer time interval from biopsy to radiotherapy does not appear to be associated with worse overall survival. However, external validation of these findings is necessary given that selection bias is a significant limitation of this study.
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Neoplasias Encefálicas , Glioblastoma , Humanos , Glioblastoma/patologia , Radioterapia Adjuvante , Biópsia , Neoplasias Encefálicas/cirurgia , Modelos de Riscos ProporcionaisRESUMO
OPINION STATEMENT: Primary malignant central nervous (CNS) tumors are a devastating group of diseases with urgent need for improved treatment options. Surgery, radiation, and cytotoxic chemotherapy remain the primary standard treatment modalities, with molecularly targeted therapies having proven efficacy in only small subsets of cases. Poly(ADP-ribose) polymerase (PARP) inhibitors, which have had immense success in the treatment of extracranial cancers with homologous recombination deficiency (HRD), are emerging as a potential targeted treatment for various CNS tumors. Although few primary CNS tumors display canonical BRCA gene defects, preclinical evidence suggests that PARP inhibitors may benefit certain CNS tumors with functional HRD or elevated replication stress. In addition, other preclinical studies indicate that PARP inhibitors may synergize with standard therapies used for CNS tumors including radiation and alkylating agents and may prevent or overcome drug resistance. Thus far, initial clinical trials with early-generation PARP inhibitors, typically as monotherapy or in the absence of selective biomarkers, have shown limited efficacy. However, the scientific rationale remains promising, and many clinical trials are ongoing, including investigations of more CNS penetrant or more potent inhibitors and of combination therapy with immune checkpoint inhibitors. Early phase trials are also critically focusing on determining active drug CNS penetration and identifying biomarkers of therapy response. In this review, we will discuss the preclinical evidence supporting use of PARP inhibitors in primary CNS tumors and clinical trial results to date, highlighting ongoing trials and future directions in the field that may yield important findings and potentially impact the treatment of these devastating malignancies in the coming years.
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Neoplasias do Sistema Nervoso Central , Neoplasias Ovarianas , Feminino , Humanos , Inibidores de Poli(ADP-Ribose) Polimerases/farmacologia , Inibidores de Poli(ADP-Ribose) Polimerases/uso terapêutico , Inibidores de Checkpoint Imunológico , Neoplasias Ovarianas/tratamento farmacológico , Poli(ADP-Ribose) Polimerases , Neoplasias do Sistema Nervoso Central/tratamento farmacológico , Neoplasias do Sistema Nervoso Central/etiologia , Biomarcadores , Alquilantes/uso terapêuticoRESUMO
Loss-of-function mutations in genes encoding the Krebs cycle enzymes Fumarate Hydratase (FH) and Succinate Dehydrogenase (SDH) induce accumulation of fumarate and succinate, respectively and predispose patients to hereditary cancer syndromes including the development of aggressive renal cell carcinoma (RCC). Fumarate and succinate competitively inhibit αKG-dependent dioxygenases, including Lysine-specific demethylase 4A/B (KDM4A/B), leading to suppression of the homologous recombination (HR) DNA repair pathway. In this study, we have developed new syngeneic Fh1- and Sdhb-deficient murine models of RCC, which demonstrate the expected accumulation of fumarate and succinate, alterations in the transcriptomic and methylation profile, and an increase in unresolved DNA double-strand breaks (DSBs). The efficacy of poly ADP-ribose polymerase inhibitors (PARPis) and temozolomide (TMZ), alone and in combination, was evaluated both in vitro and in vivo. Combination treatment with PARPi and TMZ results in marked in vitro cytotoxicity in Fh1- and Sdhb-deficient cells. In vivo, treatment with standard dosing of the PARP inhibitor BGB-290 and low-dose TMZ significantly inhibits tumor growth without a significant increase in toxicity. These findings provide the basis for a novel therapeutic strategy exploiting HR deficiency in FH and SDH-deficient RCC with combined PARP inhibition and low-dose alkylating chemotherapy.
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Carcinoma de Células Renais , Dioxigenases , Neoplasias Renais , Adenosina Difosfato Ribose , Animais , Carcinoma de Células Renais/tratamento farmacológico , Carcinoma de Células Renais/genética , Ciclo do Ácido Cítrico , DNA , Fumarato Hidratase/genética , Fumaratos , Humanos , Histona Desmetilases com o Domínio Jumonji , Neoplasias Renais/tratamento farmacológico , Neoplasias Renais/genética , Lisina , Camundongos , Poli(ADP-Ribose) Polimerase-1 , Inibidores de Poli(ADP-Ribose) Polimerases/farmacologia , Succinato Desidrogenase/genética , Succinatos , Temozolomida/farmacologiaRESUMO
Glioblastoma (GBM), the deadliest brain cancer, presents a multitude of challenges to the development of new therapies. The standard of care has only changed marginally in the past 17 years, and few new chemotherapies have emerged to supplant or effectively combine with temozolomide. Concurrently, new technologies and techniques are being investigated to overcome the pharmacokinetic challenges associated with brain delivery, such as the blood brain barrier (BBB), tissue penetration, diffusion, and clearance in order to allow for potent agents to successful engage in tumor killing. Alternative delivery modalities such as focused ultrasound and convection enhanced delivery allow for the local disruption of the BBB, and the latter in particular has shown promise in achieving broad distribution of agents in the brain. Furthermore, the development of polymeric nanocarriers to encapsulate a variety of cargo, including small molecules, proteins, and nucleic acids, have allowed for formulations that protect and control the release of said cargo to extend its half-life. The combination of local delivery and nanocarriers presents an exciting opportunity to address the limitations of current chemotherapies for GBM toward the goal of improving safety and efficacy of treatment. However, much work remains to establish standard criteria for selection and implementation of these modalities before they can be widely implemented in the clinic. Ultimately, engineering principles and nanotechnology have opened the door to a new wave of research that may soon advance the stagnant state of GBM treatment development.
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Antineoplásicos , Neoplasias Encefálicas , Glioblastoma , Humanos , Polímeros , Sistemas de Liberação de Medicamentos/métodos , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Neoplasias Encefálicas/patologia , Glioblastoma/metabolismoRESUMO
Approximately half of glioblastoma and more than two-thirds of grade II and III glioma tumors lack the DNA repair protein O6-methylguanine methyl transferase (MGMT). MGMT-deficient tumors respond initially to the DNA methylation agent temozolomide (TMZ) but frequently acquire resistance through loss of the mismatch repair (MMR) pathway. We report the development of agents that overcome this resistance mechanism by inducing MMR-independent cell killing selectively in MGMT-silenced tumors. These agents deposit a dynamic DNA lesion that can be reversed by MGMT but slowly evolves into an interstrand cross-link in MGMT-deficient settings, resulting in MMR-independent cell death with low toxicity in vitro and in vivo. This discovery may lead to new treatments for gliomas and may represent a new paradigm for designing chemotherapeutics that exploit specific DNA repair defects.
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Antineoplásicos Alquilantes , Neoplasias Encefálicas , Metilases de Modificação do DNA , Enzimas Reparadoras do DNA , Desenho de Fármacos , Resistencia a Medicamentos Antineoplásicos , Glioblastoma , Proteínas Supressoras de Tumor , Antineoplásicos Alquilantes/química , Antineoplásicos Alquilantes/farmacologia , Antineoplásicos Alquilantes/uso terapêutico , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/genética , Linhagem Celular Tumoral , Metilação de DNA/genética , Metilases de Modificação do DNA/genética , Reparo do DNA/genética , Enzimas Reparadoras do DNA/genética , Dacarbazina/farmacologia , Dacarbazina/uso terapêutico , Resistencia a Medicamentos Antineoplásicos/genética , Glioblastoma/tratamento farmacológico , Glioblastoma/genética , Humanos , Temozolomida/farmacologia , Temozolomida/uso terapêutico , Proteínas Supressoras de Tumor/genéticaRESUMO
Intrathecal delivery (IT) of opiates into the cerebrospinal fluid (CSF) for anesthesia and pain relief has been used clinically for decades, but this relatively straightforward approach of bypassing the blood-brain barrier has been underutilized for other indications because of its lack of utility in delivering small lipid-soluble drugs. However, emerging evidence suggests that IT drug delivery be an efficacious strategy for the treatment of cancers in which there is leptomeningeal spread of disease. In this review, we discuss CSF flow dynamics and CSF clearance pathways in the context of intrathecal delivery. We discuss human and animal studies of several new classes of therapeutic agents-cellular, protein, nucleic acid, and nanoparticle-based small molecules-that may benefit from IT delivery. The complexity of the CSF compartment presents several key challenges in predicting biodistribution of IT-delivered drugs. New approaches and strategies are needed that can overcome the high rates of turnover in the CSF to reach specific tissues or cellular targets.
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Barreira Hematoencefálica , Sistemas de Liberação de Medicamentos , Animais , Transporte Biológico , Barreira Hematoencefálica/metabolismo , Humanos , Imunoterapia , Distribuição TecidualRESUMO
Purpose: Whole brain radiation therapy (WBRT) is often used as an effective treatment for patients with brain metastasis, although it is also known to have deleterious cognitive effects. Multiple trials have identified strategies to help mitigate neurocognitive decline after WBRT, although there may be barriers to integrating these techniques into routine clinical practice. The aim of this study was to characterize national practice patterns related to neurocognitive preservation strategies used during WBRT. Methods and Materials: We conducted an online survey of all American Society for Radiation Oncology-registered radiation oncologists (ROs), excluding trainees, regarding their practice patterns and attitudes toward employing memantine and hippocampal avoidance whole brain radiation therapy (HA-WBRT). Pearson χ2 tests for categorical variables or Student t tests for continuous variables were used to assess associations between provider characteristics and prescribing of either memantine or HA. All statistical tests were 2-sided and a P value <.05 was considered statistically significant. Results: Among 4408 ROs invited to participate, 417 (9.5%) completed the survey. Among respondents, 79.6% reported having offered memantine, 72.7% HA-WBRT, and 63.1% both for any of their patients undergoing WBRT. Common reasons for not offering memantine included limitations of current evidence (35.3%) and concerns about adverse effects (22.4%). Common reasons for not offering HA-WBRT included resource-intensive treatment planning and treatment delay (43.9%) and concern about obtaining prior authorization (38.6%). ROs with fewer years in practice (mean 15.7 vs 23.4 years) were more likely to prescribe memantine (P < .001), whereas HA was more likely prescribed by central nervous system specialists (P < .001) and ROs in academic settings (P = .04). Conclusions: Our survey suggests that the majority of respondents offer approaches for neurocognitive preservation during WBRT for their patients. Further efforts are needed to broaden education and reduce barriers among ROs to improve implementation of neurocognitive-sparing techniques in patients undergoing WBRT.
RESUMO
The methylation status of the O6-methylguanine methyltransferase (MGMT) gene promoter has been widely accepted as a prognostic biomarker for treatment with the alkylator, temozolomide (TMZ). In the absence of promoter methylation, the MGMT enzyme removes O6-methylguanine (O6-meG) lesions. In the setting of MGMT-promoter methylation (MGMT-), the O6-meG lesion activates the mismatch repair (MMR) pathway which functions to remove the damage. Our group reported that loss of MGMT expression via MGMT promoter silencing modulates activation of ataxia telangiectasia and RAD3 related protein (ATR) in response to TMZ treatment, which is associated with synergistic tumor-cell killing. Whether or not MMR proteins are involved in ATR activation in MGMT-cells upon alkylation damage remains poorly understood. To investigate the function of MMR in ATR activation, we created isogenic cell lines with knockdowns of the individual human MMR proteins MutS homolog 2 (MSH2), MutS homolog 6 (MSH6), MutS homolog 3 (MSH3), MutL homolog 1 (MLH1), and PMS1 homolog 2 (PMS2). Here, we demonstrate that MSH2, MSH6, MLH1 and PMS2, specifically, are involved in the activation of the ATR axis after TMZ exposure, whereas MSH3 is likely not. This study elucidates a potential mechanistic understanding of how the MMR system is involved in ATR activation by TMZ in glioblastoma cells, which is important for targeting MMR-mutated cancers.
Assuntos
Glioblastoma , Antineoplásicos Alquilantes/farmacologia , Antineoplásicos Alquilantes/uso terapêutico , Proteínas Mutadas de Ataxia Telangiectasia/genética , Proteínas Mutadas de Ataxia Telangiectasia/metabolismo , Reparo de Erro de Pareamento de DNA/genética , Metilases de Modificação do DNA/genética , Metilases de Modificação do DNA/metabolismo , Enzimas Reparadoras do DNA/genética , Enzimas Reparadoras do DNA/metabolismo , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Glioblastoma/tratamento farmacológico , Glioblastoma/genética , Humanos , Metiltransferases/metabolismo , Endonuclease PMS2 de Reparo de Erro de Pareamento/genética , Proteína 1 Homóloga a MutL/genética , Proteína 1 Homóloga a MutL/metabolismo , Proteína 2 Homóloga a MutS/genética , Temozolomida/farmacologia , Temozolomida/uso terapêutico , Proteínas Supressoras de Tumor/metabolismoRESUMO
Exatecan and deruxtecan are antineoplastic camptothecin derivatives in development as tumor-targeted-delivery warheads in various formulations including peptides, liposomes, polyethylene glycol nanoparticles, and antibody-drug conjugates. Here, we report the molecular pharmacology of exatecan compared with the clinically approved topoisomerase I (TOP1) inhibitors and preclinical models for validating biomarkers and the combination of exatecan with ataxia telangiectasia and Rad3-related kinase (ATR) inhibitors. Modeling exatecan binding at the interface of a TOP1 cleavage complex suggests two novel molecular interactions with the flanking DNA base and the TOP1 residue N352, in addition to the three known interactions of camptothecins with the TOP1 residues R364, D533, and N722. Accordingly, exatecan showed much stronger TOP1 trapping, higher DNA damage, and apoptotic cell death than the classical TOP1 inhibitors used clinically. We demonstrate the value of SLFN11 expression and homologous recombination (HR) deficiency (HRD) as predictive biomarkers of response to exatecan. We also show that exatecan kills cancer cells synergistically with the clinical ATR inhibitor ceralasertib (AZD6738). To establish the translational potential of this combination, we tested CBX-12, a clinically developed pH-sensitive peptide-exatecan conjugate that selectively targets cancer cells and is currently in clinical trials. The combination of CBX-12 with ceralasertib significantly suppressed tumor growth in mouse xenografts. Collectively, our results demonstrate the potency of exatecan as a TOP1 inhibitor and its clinical potential in combination with ATR inhibitors, using SLFN11 and HRD as predictive biomarkers.
Assuntos
DNA Topoisomerases Tipo I , Neoplasias , Inibidores da Topoisomerase I , Animais , Proteínas Mutadas de Ataxia Telangiectasia/metabolismo , Camptotecina/análogos & derivados , DNA/metabolismo , DNA Topoisomerases Tipo I/metabolismo , Humanos , Camundongos , Neoplasias/tratamento farmacológico , Neoplasias/genética , Proteínas Nucleares/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Inibidores da Topoisomerase I/farmacologiaRESUMO
Treatment options for patients with relapsed/refractory acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS) are scarce. Recurring mutations, such as mutations in isocitrate dehydrogenase-1 and -2 (IDH1/2) are found in subsets of AML and MDS, are therapeutically targeted by mutant enzyme-specific small molecule inhibitors (IDHmi). IDH mutations induce diverse metabolic and epigenetic changes that drive malignant transformation. IDHmi alone are not curative and resistance commonly develops, underscoring the importance of alternate therapeutic options. We were first to report that IDH1/2 mutations induce a homologous recombination (HR) defect, which confers sensitivity to poly (ADP)-ribose polymerase inhibitors (PARPi). Here, we show that the PARPi olaparib is effective against primary patient-derived IDH1/2-mutant AML/ MDS xeno-grafts (PDXs). Olaparib efficiently reduced overall engraftment and leukemia-initiating cell frequency as evident in serial transplantation assays in IDH1/2-mutant but not -wildtype AML/MDS PDXs. Importantly, we show that olaparib is effective in both IDHmi-naïve and -resistant AML PDXs, critical given the high relapse and refractoriness rates to IDHmi. Our pre-clinical studies provide a strong rationale for the translation of PARP inhibition to patients with IDH1/2-mutant AML/ MDS, providing an additional line of therapy for patients who do not respond to or relapse after targeted mutant IDH inhibition.
Assuntos
Leucemia Mieloide Aguda , Síndromes Mielodisplásicas , Inibidores Enzimáticos/farmacologia , Humanos , Isocitrato Desidrogenase/genética , Isocitrato Desidrogenase/metabolismo , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/genética , Mutação , Síndromes Mielodisplásicas/tratamento farmacológico , Síndromes Mielodisplásicas/genética , Inibidores de Poli(ADP-Ribose) Polimerases/farmacologia , Inibidores de Poli(ADP-Ribose) Polimerases/uso terapêutico , RecidivaRESUMO
Radiation therapy continues to break down technological barriers to deliver ionizing radiation with exceptional anatomical precision. However, some tumor types and subtypes exhibit intrinsic biological resistance to radiotherapy, which can result in unsuccessful tumor eradication or symptom palliation. Radiation resistance can result from alterations in diverse genetic, epigenetic, and metabolic pathways. Therapeutic targeting of these tumor-specific alterations may provide tumor-selective radiosensitization with relative sparing of adjacent normal tissues. This issue of Seminars in Radiation Oncology presents a series of articles that describe recent progress towards genomically-directed radiosensitization.