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In Latin America, prostate cancer is the third most common cancer overall and the most common in men, with the highest mortality rate of all cancers. In 2022, there were approximately 22,985 new prostate cancer cases and 61,056 deaths from prostate cancer in the region. Patients with metastatic disease that is resistant to cure by castration now have multiple therapeutic options, including poly-ADP ribose polymerase inhibitors. These treatment advances present new challenges, such as developing monitoring protocols for early detection of disease progression to castration resistance. The Americas Health Foundation organized a 3-day meeting with 8 regional oncologists and pathologists to create a paper on metastatic castration-resistant prostate cancer diagnosis and therapy, including the new poly-ADP ribose polymerase inhibitors. The panel examined metastatic castration-resistant prostate cancer in Latin America and recommended ways to improve patient care using published literature and their expertise. Gene mutations play an important role in prostate cancer development. Precision medicine innovations highlight the importance of genotyping DNA variants and tumor biomarkers for targeted treatment. Access to appropriate genetic testing is difficult, medications are available but expensive, and there is a lack of infrastructure and regulatory frameworks that prevent patients from benefiting from innovative therapies. The panel recommends developing a population database and biobank and creating tumor tissue collection, processing, and storage facilities. Multi-stakeholder collaboration is needed to integrate the information gathered, train staff, select target populations, improve patient accessibility, and reduce the cost burden of drugs, genetic counselors, and cancer geneticists in Latin America. Collaboration is essential among healthcare professionals, policymakers, patient advocacy groups, pharmaceutical companies, and international organizations to address these challenges and needs in Latin America.
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Inibidores de Poli(ADP-Ribose) Polimerases , Neoplasias de Próstata Resistentes à Castração , Humanos , Masculino , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Neoplasias de Próstata Resistentes à Castração/patologia , Inibidores de Poli(ADP-Ribose) Polimerases/uso terapêutico , América Latina , Metástase NeoplásicaRESUMO
OBJECTIVES: No head-to-head trials had been performed to estimate the relative effectiveness of poly ADP-ribose polymerase inhibitor (PARPi) and androgen receptor signaling inhibitor (ARSi) in the first-line treatment for metastatic castration-resistant prostate cancer (mCRPC). We aimed to perform a systematic review and network meta-analysis to evaluate the comparative effectiveness of various systemic treatment agents for patients with mCRPC. METHODS: A comprehensive literature search was conducted for abstracts and full-text articles from the database's inception through April 27, 2023. The study concentrated on assessing radiographic progression-free survival (rPFS) for both overall and homologous recombination repair mutation (HRRm) population, with overall survival (OS) as the secondary measure. Under the Bayesian framework, the overall effect was pooled using the fixed-effects model in base case analysis. Scenario analysis using restricted mean survival time (RMST) methods was performed to test the robustness of the results. RESULTS: Nine studies with 6,830 patients and 8 unique treatment options were included. Network meta-analysis demonstrated that talazoparib in combination with enzalutamide (TALA + ENZA; overall population, hazard ratio [HR], 0.20; 95% credible interval [CrI]: 0.16-0.26; RMST, 3.51; 95% confidence interval [CI] 2.46-4.60; HRRm population, HR, 0.15; 95% CrI: 0.09-0.23; RMST, 4.14; 95% CI 2.84-5.39) was superior to other treatments in the first-line setting in terms of rPFS. The results of Bayesian framework and RMST models showed consistent efficacy ranks. When extrapolated to overall survival benefit, within the Bayesian framework, olaparib plus abiraterone acetate and prednisone (OLAP + AAP) achieved the highest OS benefit for the overall population, which was not statistically significant when compared to TALA + ENZA. However, TALA + ENZA achieved the highest OS benefit at 3 years by applying RMST. CONCLUSIONS: We suggest that talazoparib in combination with enzalutamide is probably a preferred treatment agent for the overall population and HRRm patients with mCRPC. Given the limitations of network framework and the modeling assumptions undertaken to finalize the analyses, results should be cautiously interpreted.
Assuntos
Antagonistas de Receptores de Andrógenos , Protocolos de Quimioterapia Combinada Antineoplásica , Inibidores de Poli(ADP-Ribose) Polimerases , Neoplasias de Próstata Resistentes à Castração , Humanos , Masculino , Acetato de Abiraterona/uso terapêutico , Antagonistas de Receptores de Andrógenos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Teorema de Bayes , Benzamidas/uso terapêutico , Metanálise em Rede , Nitrilas , Feniltioidantoína/uso terapêutico , Feniltioidantoína/análogos & derivados , Ftalazinas/uso terapêutico , Piperazinas/uso terapêutico , Inibidores de Poli(ADP-Ribose) Polimerases/uso terapêutico , Intervalo Livre de Progressão , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Neoplasias de Próstata Resistentes à Castração/patologia , Neoplasias de Próstata Resistentes à Castração/mortalidadeRESUMO
The development of resistance against photodamage triggered by photodynamic therapy (PDT) is ascribed mainly to the cellular redox defenses and repair. If the tumor tissue is not promptly eliminated by the first few PDT sessions, PDT-resistance can be favored, challenging the efficacy of the treatment. Although the mechanism of PDT resistance is still unclear, in vitro assays have evidenced that it can be developed through the PARP damage-repair signaling pathway. Therefore, inhibition of poly(adenosine diphosphate (ADP)-ribose) polymerase (PARP) has the potential to increase PDT efficacy. This work reports on the synthesis of a controlled release system of a photosensitizer, methylene blue (MB) and a PARP-inhibitor, the veliparib. MB and veliparib were co-encapsulated in poly(lactic-co-glycolic acid) (PLGA) nanoparticles (VMB-NPs). A colloidal stable aqueous suspension of nanoparticles was obtained. The average hydrodynamic diameter was 90 nm and a narrow size distribution was obtained, with a polydispersity index (PDI) of 0.08. The release kinetics of MB and veliparib from VMB-NPs showed an initial burst of 8.7% and 58.3% release of the total amounts of MB and veliparib respectively, in the first 6 h, and a delayed release of up to 11.3% and 70%, in 19 days, for MB and veliparib, respectively. The VMB-NPs showed no cytotoxicity in the dark but the viability of B16F10-Nex2 cells decreased by 36% when the cells were irradiated (102 J/cm2, 660 nm) and treated with VMB-NPs containing 1.0 µM of MB and 8.3 µM of veliparib. Considering the increased photoactivity even at low MB and veliparib concentrations and the absence of cytotoxicity in dark, the co-encapsulation of MB and veliparib was shown to be a promising strategy to improve the PDT efficacy.
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Poly (ADP-ribose) polymerase (PARP) inhibitors constitute an important treatment option for ovarian cancer nowadays. The magnitude of benefit from PARP inhibitors is influenced by the homologous recombination status, with greater benefit observed in patients with BRCA mutated or BRCA wild-type homologous recombination deficient (HRD) tumors. Although some PARP inhibitor activity has been shown in homologous recombination proficient (HRP) ovarian tumors, its clinical relevance as a single agent is unsatisfactory in this population. Furthermore, even HRD tumors present primary or secondary resistance to PARP inhibitors. Strategies to overcome treatment resistance, as well as to enhance PARP inhibitors' efficacy in HRP tumors, are highly warranted. Diverse combinations are being studied with this aim, including combinations with antiangiogenics, immunotherapy, and other targeted therapies. This review discusses the rationale for developing therapy combinations with PARP inhibitors, the current knowledge, and the future perspectives on this issue.
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Metastatic pancreatic ductal adenocarcinoma (PDAC) has a dismal prognosis. Until recently, cytotoxic chemotherapy was the only treatment option. Currently, there are subgroups of patients with PDAC either with somatic or germline mutations who are candidates for targeted agents. Germline mutations in the BRCA1 and BRCA2 genes promote the incapacity of tumor cells to recover from DNA-accumulated damage caused by cytotoxic drugs, like platinum agents, and, most recently, through a diverse process by poly(adenosine diphosphate-ribose) polymerase inhibitor (PARPi). A 59-year-old female who was treated for a triple negative breast cancer 8 years ago with surgery, adjuvant chemotherapy and radiotherapy, presented with increasing back pain. Investigation revealed multiple liver nodules and a large mass in the head of the pancreas. Biopsy confirmed PDAC. She received 13 cycles of FOLFIRINOX, achieving partial response both in the liver and pancreatic lesion, with resolution of symptoms. Due to increasing neuropathy, chemotherapy was stopped, and the patient was followed. Sixteen months later, her CA19-9 levels increased. Given limiting neuropathy, the patient was restarted on FOLFIRI only. After 8 cycles, there was disease progression plus uncontrolled back pain. A mutational test was requested and confirmed a BRCA1 germline mutation. The patient was started on olaparib. After 3 cycles, images showed a significant response and after 6 cycles, it remained stable, with persistent fall in CA19-9 levels. She is currently on treatment, with ongoing response. In conclusion, patients with metastatic PDAC and BRCA mutation may benefit from PARPi even after progression on chemotherapy. We hypothesize that olaparib works even in the setting of disease progression and not solely as a maintenance therapy following platinum-based therapy. Randomized trials are needed investigating the role of olaparib following disease progression in PDAC.
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INTRODUCTION: More than the twenty percent of ovarian cancers are hereditary, and most have BRCA mutations. The 30% of Mexican patients with the BRCA1 mutation have the BRCA1 gene exon 9-12del deletion founder mutation (BRCA1 ex9-12del). BRCA-mutated tumors are more sensitive to PARP inhibitors such as olaparib. OBJECTIVE: To show the clinical experience on the use of olaparib at Instituto Nacional de Cancerología in Mexico. METHOD: Ovarian cancer patients treated with olaparib from November 2016 to December 2018 were studied, and their characteristics, clinical response, progression-free survival (PFS) and toxicities were described. RESULTS: Nineteen patients were assessed, with BRCA1 mutation being found in 78.9%, out of which 21.1% were carriers of the ex9-12del founder mutation. The median of PFS was 12 months; for patients treated on second and third line it was > 15 months, and for those treated with a fourth and subsequent line it was 8.3 months. Patients with the founder mutation had better results. Toxicities were like those reported in previous studies. CONCLUSIONS: Olaparib offers greater PFS benefit as maintenance therapy after a first and second relapse. Patients with founder mutation have had sustained PFS.
INTRODUCCIÓN: Más del 20 % de los cánceres de ovario puede ser hereditario y la mayoría tiene mutaciones BRCA. El 33 % de las pacientes mexicanas con mutación BRCA1 tiene la mutación fundadora deleción del exón 9-12del del gen BRCA1 (BRCA1 ex9-12del). Los tumores BRCA mutados son más sensibles a inhibidores PARP como olaparib. OBJETIVO: Mostrar la experiencia clínica del uso de olaparib en el Instituto Nacional de Cancerología de México. MÉTODO: Se estudiaron las pacientes con cáncer de ovario tratadas con olaparib de noviembre de 2016 a diciembre de 2018 y se describieron sus características, respuesta clínica, supervivencia libre de progresión y toxicidades. RESULTADOS: Se evaluaron 19 pacientes, 78.9 % presentó mutación BRCA1, del cual 21.1 % era portador de la mutación fundadora ex9-12del. La mediana de supervivencia libre de progresión global fue de 12 meses, para las pacientes tratadas tratadas con olaparib de mantenimiento posterior a segunda y tercera línea fue de > 15 meses y para las de cuarta línea o más fue de 8.3 meses. Las pacientes con mutación fundadora presentaron mejores respuestas. Las toxicidades fueron similares a las de estudios con el uso de olaparib. CONCLUSIONES: Olaparib ofrece mayor beneficio en supervivencia libre de progresión como tratamiento de mantenimiento después de la primera y segunda recaída. Las pacientes con mutación fundadora han tenido respuesta sostenida.
Assuntos
Proteína BRCA1/genética , Neoplasias Ovarianas/tratamento farmacológico , Ftalazinas/administração & dosagem , Piperazinas/administração & dosagem , Inibidores de Poli(ADP-Ribose) Polimerases/administração & dosagem , Adulto , Idoso , Feminino , Humanos , México , Pessoa de Meia-Idade , Mutação , Recidiva Local de Neoplasia , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/patologia , Ftalazinas/efeitos adversos , Piperazinas/efeitos adversos , Inibidores de Poli(ADP-Ribose) Polimerases/efeitos adversos , Intervalo Livre de ProgressãoRESUMO
Due to their unique and versatile biochemical properties, ruthenium-based compounds have emerged as promising anticancer agents. Previous studies showed that three ruthenium(II) compounds: [Ru(pySH)(bipy)(dppb)]PF6 (1), [Ru(HSpym)(bipy)(dppb)]PF6 (2) and Ru[(SpymMe2)(bipy)(dppb)]PF6 (3) presented anticancer properties higher than doxorubicin and cisplatin and acted as human topoisomerase IB (Topo I) inhibitors. Here, we focused our studies on in vitro intestinal permeability and anticancer mechanisms of these three complexes. Caco-2 permeation studies showed that 1 did not permeate the monolayer of intestinal cells, suggesting a lack of absorption on oral administration, while 2 and 3 permeated the cells after 60 and 120 min, respectively. Complexes 2 and 3 fully inhibited Topo II relaxation activity at 125 µM. In previously studies, 3 was the most potent inhibitor of Topo I, here, we concluded that it is a dual topoisomerase inhibitor. Moreover, it presented selectivity to cancer cells when evaluated by clonogenic assay. Thus, 3 was selected to gene expression assay front MDA-MB-231 cells from triple-negative breast cancer (TNBC), which represents the highly aggressive subgroup of breast cancers with poor prognosis. The analyses revealed changes of 27 out of 84 sought target genes. PARP1 and PARP2 were 5.29 and 1.83 times down-regulated after treatment with 3, respectively. PARPs have been attractive antitumor drug targets, considering PARP inhibition could suppress DNA damage repair and sensitize tumor cells to DNA damage agents. Recent advances in DNA repair studies have shown that an approach that causes cell lethality using synthetic PARP-inhibiting drugs has produced promising results in TNBC.
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Antineoplásicos/farmacologia , Complexos de Coordenação/farmacologia , Inibidores de Poli(ADP-Ribose) Polimerases/farmacologia , Rutênio/farmacologia , Inibidores da Topoisomerase II/farmacologia , Antineoplásicos/química , Células CACO-2 , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Complexos de Coordenação/química , DNA Topoisomerases Tipo II/metabolismo , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Inibidores de Poli(ADP-Ribose) Polimerases/química , Poli(ADP-Ribose) Polimerases/metabolismo , Rutênio/química , Relação Estrutura-Atividade , Inibidores da Topoisomerase II/químicaRESUMO
Glioblastoma (GBM) is fatal. The standard radiotherapy and chemotherapy (temozolomide) followed by an adjuvant phase of temozolomide provide patients with, on average, a 2.5 months benefit. New treatments that can improve sensitivity to the standard treatment are urgently needed. Herein, we review the mechanisms and utility of poly (ADP-ribose) polymerase inhibitors in combination with radiation therapy as a treatment option for GBM patients and the role of phosphatase and tensin homologue mutations as a biomarker of response.