RESUMO
BACKGROUND: GP-2250, a novel analog of taurultam (TRLT), has emerged as a potent anti-neoplastic drug; however, the mechanisms underlying its effects are not well understood. Here, we investigated the mechanism of action and the biological effects of GP-2250 using in vitro and in vivo models. METHODS: We carried out a series of in vitro (MTT assay, Annexin V/PI assay, colony formation assay, reverse-phase protein array [RPPA], and HRLC/IC analysis) to determine the biological activity of GP-2250 and investigate the mechanism of action. In vivo experiments were carried out to determine the therapeutic efficacy of GP-2250 alone and in combination with standard-of-care drugs (e.g., paclitaxel, cisplatin, topotecan, and poly ADP-ribose polymerase [PARP] inhibitors). RESULTS: We investigated the cytotoxic effect of GP-2250 in 10 ovarian cancer cell lines and found GP-2250 combined with a PARP inhibitor had the greatest synergy. RPPA revealed that GP-2250 inhibited hypoxia-inducible factor-1α, AKT, and mammalian target of rapamycin (mTOR) activation and expression. High-resolution mass spectrometry revealed that hexokinase2 activity and protein expression were significantly reduced by GP-2250 exposure. Furthermore, GP-2250 reduced glycolysis and ATP synthesis in cancer cells. An in vivo pharmacodynamic experiment using the OVCAR8 mouse model demonstrated that 500 mg/kg GP-2250 was effective in downregulating AKT and mTOR activation and expression. In the in vivo therapy experiment using an orthotopic mouse model, a combination of GP-2250 with either PARP inhibitors or bevacizumab showed a significant reduction of tumor weights and nodules compared to those treated with a vehicle, control IgG groups, or monotherapy groups. CONCLUSIONS: Taken together, our data indicate that GP-2250 exerts profound effects on tumor metabolism and, in combination with PARP inhibitors or bevacizumab, showed promising anti-tumor efficacy. These findings could have implications for the clinical development of GP-2250.
Assuntos
Neoplasias Ovarianas , Ensaios Antitumorais Modelo de Xenoenxerto , Animais , Feminino , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/patologia , Neoplasias Ovarianas/metabolismo , Humanos , Camundongos , Linhagem Celular Tumoral , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Sinergismo Farmacológico , Apoptose/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Antineoplásicos/farmacologia , Modelos Animais de Doenças , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Serina-Treonina Quinases TOR/metabolismo , Inibidores de Poli(ADP-Ribose) Polimerases/farmacologia , Inibidores de Poli(ADP-Ribose) Polimerases/uso terapêuticoRESUMO
BACKGROUND: Few studies have evaluated the role of cytoreductive surgery in patients with recurrent adult granulosa cell tumors of the ovary. Despite a multitude of treatment modalities in the recurrent setting, the optimal management strategy is not known. Cytoreductive surgery offers an attractive option for disease confined to the abdomen/pelvis. However, few studies have evaluated the role of surgery compared with systemic therapy alone following the first recurrence and subsequent disease progressions. OBJECTIVE: This study aimed to determine the impact of secondary, tertiary, and quaternary cytoreductive surgery on survival outcomes in recurrent adult granulosa cell tumors of the ovary. STUDY DESIGN: This is a multicenter, retrospective cohort study evaluating patients with recurrent adult granulosa cell tumors of the ovary enrolled in the MD Anderson Rare Gynecologic Malignancy Registry from 1970 to 2022. Study inclusion criteria consisted of histology-proven recurrent disease, at least 1 documented recurrence, and treatment/treatment planning at the MD Anderson Cancer Center or Lyndon B. Johnson General Hospital. The primary exposure was cytoreductive surgery, and the outcomes of interest were progression-free survival and overall survival. Survival analyses were restricted to eligible patients with resectable disease without medical barriers to surgery at each progression episode. Demographic and clinicopathologic characteristics were summarized using descriptive statistics. Progression-free survival (after first, second, and third progression) and overall survival were estimated with methods of Kaplan and Meier, and were modeled via Cox proportional hazards regression. Multivariable analyses were performed for progression-free survival after first progression and overall survival. RESULTS: Among the 369 patients with adult granulosa cell tumors of the ovary in the registry, 149 patients met the study inclusion criteria. Secondary cytoreductive surgery was associated with a significant improvement in progression-free survival on univariable (hazard ratio, 0.37; 95% confidence interval, 0.17-0.81, P=.01) and multivariable analyses (hazard ratio, 0.42; 95% confidence interval, 0.19-0.92; P=.03). Those who underwent secondary cytoreductive surgery had a significantly improved median overall survival compared with those who did not undergo cytoreductive surgery (181.92 vs 61.56 months, respectively; P=.002). Overall survival benefit remained statistically significant on multivariable analysis (hazard ratio, 0.28; 95% confidence interval, 0.11-0.67; P=.004). Tertiary cytoreductive surgery was similarly associated with a significant improvement in progression-free survival (hazard ratio, 0.43; 95% confidence interval, 0.26-0.70; P=.001). Despite a similar trend, quaternary cytoreductive surgery was not associated with a significant improvement in progression-free survival (hazard ratio, 0.74; 95% confidence interval, 0.42-1.26; P=.27). CONCLUSION: Among those with resectable disease and no medical contraindications to surgery, cytoreductive surgery may have a beneficial impact on progression-free survival and overall survival in patients with recurrent adult granulosa cell tumors of the ovary.
Assuntos
Procedimentos Cirúrgicos de Citorredução , Tumor de Células da Granulosa , Recidiva Local de Neoplasia , Neoplasias Ovarianas , Humanos , Feminino , Tumor de Células da Granulosa/cirurgia , Tumor de Células da Granulosa/mortalidade , Tumor de Células da Granulosa/patologia , Estudos Retrospectivos , Pessoa de Meia-Idade , Adulto , Neoplasias Ovarianas/cirurgia , Neoplasias Ovarianas/mortalidade , Neoplasias Ovarianas/patologia , Idoso , Intervalo Livre de Progressão , Estudos de Coortes , Sistema de Registros , Taxa de SobrevidaRESUMO
The pathogenesis of cutaneous T-cell lymphoma (CTCL) remains unclear. Using single-cell RNA or T-cell receptor (TCR) sequencing of 32 619 CD3+CD4+ and CD26+/CD7+ and 29 932 CD3+CD4+ and CD26-/CD7- lymphocytes from the peripheral blood of 7 patients with CTCL, coupled to single-cell ATAC-sequencing of 26,411 CD3+CD4+ and CD26+/CD7+ and 33 841 CD3+CD4+ and CD26-/CD7- lymphocytes, we show that tumor cells in Sézary syndrome and mycosis fungoides (MF) exhibit different phenotypes and trajectories of differentiation. When compared to MF, Sézary cells exhibit narrower repertoires of TCRs and exhibit clonal enrichment. Surprisingly, we identified ≥200 mutations in hematopoietic stem cells from multiple patients with Sézary syndrome. Mutations in key oncogenes were also present in peripheral Sézary cells, which also showed the hallmarks of recent thymic egression. Together our data suggest that CTCL arises from mutated lymphocyte progenitors that acquire TCRs in the thymus, which complete their malignant transformation in the periphery.
Assuntos
Linfoma Cutâneo de Células T , Micose Fungoide , Síndrome de Sézary , Neoplasias Cutâneas , Humanos , Síndrome de Sézary/genética , Síndrome de Sézary/patologia , Dipeptidil Peptidase 4 , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/patologia , Micose Fungoide/genética , Micose Fungoide/patologia , Linfoma Cutâneo de Células T/genética , Receptores de Antígenos de Linfócitos TRESUMO
OBJECTIVE: To demonstrate that shared antibody responses in endometriosis and endometriosis-associated ovarian cancer spontaneously antagonize malignant progression and can be leveraged to develop future immunotherapies. METHODS: B cells from cyopreserved clear cell ovarian carcinoma (CCC, n = 2), endometrioid ovarian carcinoma (EC, n = 2), and endometriomas (n = 2) were isolated, activated, and EBV-immortalized. Antibodies were purified from B cell supernatants and used for screening arrays containing most of the human proteome. Targets were prioritized based on accessibility (transmembrane or secreted proteins), expression in endometriosis and cancer, and concurrent IgA and IgG responses. We focused on antibodies targeting tumor-promoting syndecan binding protein (SDCBP) to demonstrate anti-tumor activity. Immunoblots and qPCR were performed to assess SDCBP expression in ovarian cancer and endometriosis cell lines and tumor samples. Recombinant IgG4 was generated using the variable heavy and light chains of dominant B cell receptors (BCRs) reacting against the extracellular domain of SDCBP, and used in in vivo studies in human CCC- and high-grade serous ovarian carcinoma (HGSOC)-bearing immunodeficient mice. RESULTS: Nine accessible proteins detected by both IgA and IgG were identified in all samples - including SDCBP, which is expressed in ovarian carcinomas of multiple histologies. Administration of α-SDCBP IgG4 in OVCAR3 (HGSOC), TOV21G and RMG-I (CCC) tumor-bearing mice significantly decreased tumor volume compared to control irrelevant IgG4. CONCLUSIONS: Spontaneous antibody responses exert suboptimal but measurable immune pressure against malignant progression in ovarian carcinomas. Using tumor-derived antibodies for developing novel immunotherapeutics warrants further investigation.
Assuntos
Adenocarcinoma de Células Claras , Carcinoma Endometrioide , Endometriose , Neoplasias Ovarianas , Humanos , Feminino , Animais , Camundongos , Neoplasias Ovarianas/patologia , Apoptose , Formação de Anticorpos , Linhagem Celular Tumoral , Carcinoma Epitelial do Ovário , Carcinoma Endometrioide/patologia , Imunoglobulina A/metabolismo , Adenocarcinoma de Células Claras/patologia , Sinteninas/metabolismoRESUMO
BACKGROUND: The optimal treatment of recurrent ovarian granulosa cell tumors is not known. Preclinical studies and small case series have suggested direct antitumor activity of gonadotropin-releasing hormone agonists in the treatment of this disease, but little is known about the efficacy and safety of this approach. OBJECTIVE: This study aimed to describe patterns of use and clinical outcomes of leuprolide acetate in a cohort of patients with recurrent granulosa cell tumors. STUDY DESIGN: This was a retrospective cohort study of patients enrolled in the Rare Gynecologic Malignancy Registry at a large cancer referral center and affiliated county hospital. Patients meeting inclusion criteria had a diagnosis of recurrent granulosa cell tumor and received either leuprolide acetate or traditional chemotherapy as cancer treatment. Outcomes were separately examined for leuprolide acetate used as adjuvant treatment, maintenance therapy, and the treatment of gross disease. Demographic and clinical data were summarized using descriptive statistics. Progression-free survival was calculated from the initiation of treatment to the date of disease progression or death, and compared between groups with the log-rank test. The 6-month clinical benefit rate was defined as the percentage of patients without disease progression 6 months after starting therapy. RESULTS: Sixty-two patients received a total of 78 leuprolide acetate-containing therapy courses, owing to 16 instances of retreatment. Of these 78 courses, 57 (73%) were for treatment of gross disease, 10 (13%) were adjuvant to tumor reductive surgery, and 11 (14%) were for maintenance therapy. Patients had received a median of 2 (interquartile range, 1-3) systemic therapy regimens before their first leuprolide acetate treatment. Tumor reductive surgery (100% [62/62]) and platinum-based chemotherapy (81% [50/62]) were common before first leuprolide acetate exposure. The median duration of leuprolide acetate therapy was 9.6 months (interquartile range, 4.8-16.5). Nearly half of the therapy courses were single-agent leuprolide acetate (49% [38/78]). Combination regimens most often included an aromatase inhibitor (23% [18/78]). Disease progression was the most common cause of discontinuation (77% [60/78]); only 1 patient (1%) discontinued leuprolide acetate because of adverse events. In the treatment of gross disease, the 6-month clinical benefit rate for first use of leuprolide acetate was 66% (95% confidence interval, 54-82). Median progression-free survival was not statistically different compared with that which followed chemotherapy (10.3 months [95% confidence interval, 8.0-16.0] vs 8.0 months [95% confidence interval, 5.0-15.3]; P=.3). CONCLUSION: In a large cohort of patients with recurrent granulosa cell tumors, the 6-month clinical benefit rate of first-time leuprolide acetate treatment of gross disease was 66% and progression-free survival was comparable to patients treated with chemotherapy. Leuprolide acetate regimens were heterogeneous, but significant toxicity was rare. These results support leuprolide acetate as safe and effective for the treatment of relapsed adult granulosa cell tumors in the second line and beyond.
Assuntos
Tumor de Células da Granulosa , Neoplasias Ovarianas , Adulto , Feminino , Humanos , Leuprolida/uso terapêutico , Tumor de Células da Granulosa/tratamento farmacológico , Estudos Retrospectivos , Progressão da Doença , Neoplasias Ovarianas/tratamento farmacológicoRESUMO
OBJECTIVE: A novel classification system of high-grade serous ovarian carcinoma based on gross morphology observed at pre-treatment laparoscopy was recently defined. The purpose of this study was to identify radiographic features unique to each morphologic subtype. METHODS: This retrospective study included 109 patients with high-grade serous ovarian cancer who underwent pre-operative computed tomography (CT) scanning and laparoscopic assessment of disease burden between 1 April 2013 and 5 August 2015. Gross morphologic subtype had been previously assigned by laparoscopy. Two radiologists independently reviewed CT images for each patient, categorized disease at eight anatomic sites, and assessed for radiographic characteristics of interest: large infiltrative plaques, mass-like metastases, enhancing peritoneal lining, architectural distortion, fat stranding, calcifications, and lymph node involvement. Demographic and clinical information was summarized with descriptive statistics and compared using Student's t-tests, χ² tests, or Fisher exact tests as appropriate; kappa statistics were used to assess inter-reader agreement. RESULTS: Certain radiographic features were found to be associated with gross morphologic subtype. Large infiltrative plaques were more common in type 1 disease (88.7% (47/53) vs 71.4% (25/35), p=0.04), while mass-like metastases were more often present in type 2 disease (48.6% (17/35) vs 22.6% (12/53), p=0.01). Additionally, radiographic presence of disease at the falciform ligament was more common in type 1 morphology (33.9% (19/56) vs 13.2% (5/38), p=0.02). CONCLUSION: Morphologic subtypes of high-grade serous ovarian cancer were associated with specific CT findings, including the presence of large infiltrative plaques, mass-like metastases, and falciform ligament involvement.
Assuntos
Cistadenocarcinoma Seroso , Neoplasias Ovarianas , Neoplasias Peritoneais , Humanos , Feminino , Neoplasias Ovarianas/patologia , Estudos Retrospectivos , Linfonodos/patologia , Neoplasias Peritoneais/cirurgia , Tomografia Computadorizada por Raios X/métodos , Cistadenocarcinoma Seroso/patologiaRESUMO
Importance: Despite similar histologic appearance among high-grade serous ovarian cancers (HGSOCs), clinical observations suggest vast differences in gross appearance. There is currently no systematic framework by which to classify HGSOCs according to their gross morphologic characteristics. Objective: To develop and characterize a gross morphologic classification system for HGSOC. Design, Setting, and Participants: This cohort study included patients with suspected advanced-stage ovarian cancer who presented between April 1, 2013, and August 5, 2016, to the University of Texas MD Anderson Cancer Center, a large referral center. Patients underwent laparoscopic assessment of disease burden before treatment and received a histopathologic diagnosis of HGSOC. Researchers assigning morphologic subtype and performing molecular analyses were blinded to clinical outcomes. Data analysis was performed between April 2020 and November 2021. Exposures: Gross tumor morphologic characteristics. Main Outcomes and Measures: Clinical outcomes and multiomic profiles of representative tumor samples of type I or type II morphologic subtypes were compared. Results: Of 112 women (mean [SD] age 62.7 [9.7] years) included in the study, most patients (84% [94]) exhibited a predominant morphologic subtype and many (63% [71]) had a uniform morphologic subtype at all involved sites. Compared with those with uniform type I morphologic subtype, patients with uniform type II morphologic subtype were more likely to have a favorable Fagotti score (83% [19 of 23] vs 46% [22 of 48]; P = .004) and thus to be triaged to primary tumor reductive surgery. Similarly, patients with uniform type II morphologic subtype also had significantly higher mean (SD) estimated blood loss (639 [559; 95% CI, 391-887] mL vs 415 [527; 95% CI, 253-577] mL; P = .006) and longer mean (SD) operative time (408 [130; 95% CI, 350-466] minutes vs 333 [113; 95% CI, 298-367] minutes; P = .03) during tumor reductive surgery. Type I tumors had enrichment of epithelial-mesenchymal transition (false discovery rate [FDR] q-value, 3.10 × 10-24), hypoxia (FDR q-value, 1.52 × 10-5), and angiogenesis pathways (FDR q-value, 2.11 × 10-2), whereas type II tumors had enrichment of pathways related to MYC signaling (FDR q-value, 2.04 × 10-9) and cell cycle progression (FDR q-value, 1.10 × 10-5) by integrated proteomic and transcriptomic analysis. Abundances of metabolites and lipids also differed between the 2 morphologic subtypes. Conclusions and Relevance: This study identified 2 novel, gross morphologic subtypes of HGSOC, each with unique clinical features and molecular signatures. The findings may have implications for triaging patients to surgery or chemotherapy, identifying outcomes, and developing tailored therapeutic strategies.
Assuntos
Neoplasias Ovarianas , Estudos de Coortes , Feminino , Humanos , Lipídeos , Pessoa de Meia-Idade , Neoplasias Ovarianas/patologia , Proteômica , Proteínas Proto-Oncogênicas c-myc/metabolismo , Transdução de SinaisRESUMO
Although chimeric antigen receptor (CAR)-expressing T cells have proven success in hematologic malignancies, their effectiveness in solid tumors has been largely unsuccessful thus far. We found that some olfactory receptors are expressed in a variety of solid tumors of different histologic subtypes, with a limited pattern of expression in normal tissues. Quantification of OR2H1 expression by qRT-PCR and Western blot analysis of 17 normal tissues, 82 ovarian cancers of various histologies, eight non-small cell lung cancers (NSCLCs), and 17 breast cancers demonstrated widespread OR2H1 expression in solid epithelial tumors with expression in normal human tissues limited to the testis. CAR T cells recognizing the extracellular domain of the olfactory receptor OR2H1 were generated with a targeting motif identified through the screening of a phage display library and demonstrated OR2H1-specific cytotoxic killing in vitro and in vivo, using tumor cells with spontaneous expression of variable OR2H1 levels. Importantly, recombinant OR2H1 IgG generated with the VH/VL sequences of the CAR construct specifically detected OR2H1 protein signal in 60 human lung cancers, 40 ovarian carcinomas, and 73 cholangiocarcinomas, at positivity rates comparable with mRNA expression and without OR2H1 staining in 58 normal tissues. CRISPR/Cas9-mediated ablation of OR2H1 confirmed targeting specificity of the CAR and the tumor-promoting role of OR2H1 in glucose metabolism. Therefore, T cells redirected against OR2H1-expressing tumor cells represent a promising therapy against a broad range of epithelial cancers, likely with an admissible toxicity profile.
Assuntos
Neoplasias Pulmonares , Neoplasias Epiteliais e Glandulares , Neoplasias Ovarianas , Receptores Odorantes , Feminino , Humanos , Linhagem Celular Tumoral , Imunoterapia Adotiva , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/terapia , Neoplasias Epiteliais e Glandulares/metabolismo , Neoplasias Ovarianas/metabolismo , Receptores Odorantes/metabolismo , Linfócitos TRESUMO
OBJECTIVE: To assess the impact of frailty in patients with ovarian cancer on surgical procedures and outcomes. METHODS: A retrospective review of patients with stage II-IV ovarian cancer from April 2013 to September 2017 was performed. Patients were triaged by laparoscopy to determine primary resectability. The adjusted modified frailty index score (amFI) was calculated and amFI ≥2 classified as high frailty. Clinical outcomes, progression free survival (PFS) and overall survival (OS) were estimated. RESULTS: 592 patients met inclusion criteria; amFI of 0, 1 and ≥ 2 was noted in 57%, 29%, and 14%, respectively. Patients with high frailty were less likely to be offered laparoscopic assessment for primary surgery (49% v. 43% v. 28% for amFI = 0, 1, and ≥ 2, p = 0.004), and more likely to have a Fagotti score ≥ 8 (58%, 48%, and 34%, p = 0.04). Only 17% of the high frailty cohort had primary tumor reductive surgery compared to 26% and 34% in patients with amFI = 1 and amFI = 0 (p = 0.02). Furthermore, patients with higher amFI were less likely to undergo any tumor reductive surgery (85% v. 74% v. 59%, p < 0.001). Postoperative complications were more frequent in patients with higher amFI (44% v. 56% v. 64%, p = 0.01). Death within thirty days of treatment initiation was significantly higher in patients with high frailty (0.4% v. 2% v. 9%, p = 0.005). In multivariate analysis, high frailty was associated with worse PFS (p = 0.02) and OS (p < 0.05). CONCLUSIONS: Postoperative morbidity, PFS, and OS were worse in patients with high frailty scores. Quantification of frailty may be useful for clinical decision making in patients with newly diagnosed advanced ovarian cancer.
Assuntos
Fragilidade , Neoplasias Ovarianas , Feminino , Fragilidade/epidemiologia , Humanos , Laparoscopia , Estadiamento de Neoplasias , Neoplasias Ovarianas/patologia , Neoplasias Ovarianas/cirurgia , Complicações Pós-Operatórias/epidemiologia , Estudos Retrospectivos , Índice de Gravidade de Doença , Resultado do TratamentoRESUMO
OBJECTIVE: To determine the clinical characteristics of patients who attained pathologic complete response (pCR) after neoadjuvant chemotherapy (NACT) and to identify specific predictive or prognostic factors associated with pCR. METHODS: Two distinct populations of patients who underwent NACT followed by interval tumor reductive surgery (TRS) were used in this retrospective study. The first contained 472 patients from a single institution. The second contained only pCR patients (67); those identified from population one, plus 44 obtained through collaborative institutions. Cox analysis and log-rank tests were performed to assess associations between clinical characteristics and pCR outcome, recurrence-free survival (RFS), and overall survival (OS). RESULTS: The median RFS and OS in our pCR-only population was 24.2 and 80.8 months, respectively, with a median follow-up time of 32.4 months. In our single institution population, 23 patients attained pCR (4.9%) and had longer RFS compared to non-pCR patients with viable microscopic, optimal, or suboptimal residual disease (24.3 vs. 12.1 vs. 11.6 vs. 9.6 months, p = 0.025, 0.012, 0.008, respectively), and longer OS compared to those with optimal or suboptimal residual disease (54.5 vs. 29.4 vs. 25.7 months, p = 0.027, 0.007, respectively). Patients were more than three-fold likely to attain pCR if their CA125 value was normal at the time of surgery (OR 3.54, 95% CI: 1.14-11.05, p = 0.029). CONCLUSIONS: Women with pCR after NACT have significantly longer RFS compared to those with residual viable tumor at the time of interval tumor-reductive surgery, and CA125 is plausible biomarker for identifying these extreme responders preoperatively.
Assuntos
Terapia Neoadjuvante , Neoplasias Ovarianas , Carcinoma Epitelial do Ovário/tratamento farmacológico , Quimioterapia Adjuvante , Feminino , Humanos , Estadiamento de Neoplasias , Neoplasia Residual/patologia , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/cirurgia , Estudos RetrospectivosRESUMO
CRM1 inhibitors have demonstrated antitumor effects in ovarian and other cancers; however, rational combinations are largely unexplored. We performed a high-throughput drug library screen to identify drugs that might combine well with selinexor in ovarian cancer. Next, we tested the combination of selinexor with the top hit from the drug screen in vitro and in vivo Finally, we assessed for mechanisms underlying the identified synergy using reverse phase protein arrays (RPPA). The drug library screen assessing 688 drugs identified olaparib (a PARP inhibitor) as the most synergistic combination with selinexor. Synergy was further demonstrated by MTT assays. In the A2780luc ip1 mouse model, the combination of selinexor and olaparib yielded significantly lower tumor weight and fewer tumor nodules compared with the control group (P < 0.04 and P < 0.03). In the OVCAR5 mouse model, the combination yielded significantly fewer nodules (P = 0.006) and markedly lower tumor weight compared with the control group (P = 0.059). RPPA analysis indicated decreased expression of DNA damage repair proteins and increased expression of tumor suppressor proteins in the combination treatment group. Collectively, our preclinical findings indicate that combination with selinexor to expand the utility and efficacy of PARP inhibitors in ovarian cancer warrants further exploration.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Ensaios de Triagem em Larga Escala/métodos , Hidrazinas/uso terapêutico , Neoplasias Ovarianas/tratamento farmacológico , Ftalazinas/uso terapêutico , Piperazinas/uso terapêutico , Triazóis/uso terapêutico , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Linhagem Celular Tumoral , Modelos Animais de Doenças , Feminino , Humanos , Hidrazinas/farmacologia , Camundongos , Camundongos Nus , Neoplasias Ovarianas/patologia , Ftalazinas/farmacologia , Piperazinas/farmacologia , Triazóis/farmacologiaRESUMO
In ovarian cancer, platelet extravasation into the tumor and resulting metastasis is thought to be regulated mostly by the vascular endothelium. Because it is difficult to dissect complex underlying events in murine models, organ-on-a-chip methodology is applied to model vascular and platelet functions in ovarian cancer. This system (OvCa-Chip) consists of microfluidic chambers that are lined by human ovarian tumor cells interfaced with a 3-dimensional endothelialized lumen. Subsequent perfusion with human platelets within the device's vascular endothelial compartment under microvascular shear conditions for 5 days uncovered organ-to-molecular-level contributions of the endothelium to triggering platelet extravasation into tumors. Further, analysis of effluents available from the device's individual tumor and endothelial chambers revealed temporal dynamics of vascular disintegration caused by cancer cells, a differential increase in cytokine expression, and an alteration of barrier maintenance genes in endothelial cells. These events, when analyzed within the device over time, made the vascular tissue leaky and promoted platelet extravasation. Atorvastatin treatment of the endothelial cells within the OvCa-Chip revealed improved endothelial barrier function, reduction in inflammatory cytokines and, eventually, arrest of platelet extravasation. These data were validated through corresponding observations in patient-derived tumor samples. The OvCa-Chip provides a novel in vitro dissectible platform to model the mechanisms of the cancer-vascular-hematology nexus and the analyses of potential therapeutics.
Assuntos
Endotélio Vascular , Neoplasias Ovarianas , Animais , Plaquetas , Células Endoteliais , Feminino , Humanos , CamundongosRESUMO
XPO1 inhibitors have shown promise in cancer treatment, but mechanisms of resistance to these drugs are not well understood. In this study, we established selective inhibitors of nuclear export (SINE)-resistant ovarian cancer cell lines from in vivo mouse tumors and determined the mechanisms of adaptive XPO1 inhibitor resistance using protein and genomic arrays. Pathway analyses revealed upregulation of the NRG1/ERBB3 pathway in SINE-resistant cells. Depletion of ERBB3 using siRNAs restored the antitumor effect of SINE in vitro and in vivo Furthermore, exogenous NRG1 decreased the antitumor effect of SINE in ovarian cancer cell lines with high ERBB3 expression, but not in those with low expression. These results suggest that NRG1 and ERBB3 expression is a potential biomarker of response to SINE treatment. The antitumor effect of SINE was reduced by exogenous NRG1 in an ERBB3-dependent manner. These findings suggest that NRG1 and ERBB3 are effective biomarkers that should be evaluated in future clinical trials and are relevant therapeutic targets for the treatment of SINE-resistant cancers.
Assuntos
Resistencia a Medicamentos Antineoplásicos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Hidrazinas/farmacologia , Carioferinas/antagonistas & inibidores , Neuregulina-1/metabolismo , Neoplasias Ovarianas/tratamento farmacológico , Receptor ErbB-3/metabolismo , Receptores Citoplasmáticos e Nucleares/antagonistas & inibidores , Triazóis/farmacologia , Animais , Apoptose , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Proliferação de Células , Feminino , Perfilação da Expressão Gênica , Humanos , Camundongos , Camundongos Nus , Neuregulina-1/genética , Neoplasias Ovarianas/metabolismo , Neoplasias Ovarianas/patologia , Receptor ErbB-3/genética , Transcriptoma/efeitos dos fármacos , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto , Proteína Exportina 1RESUMO
OBJECTIVES: To evaluate the safety and preliminary efficacy of demcizumab (DLL4 targeted IgG2 humanized monoclonal antibody; potent inhibitor of the Notch pathway) in combination with weekly paclitaxel in platinum-resistant epithelial ovarian cancer (EOC); and to determine the maximum tolerated dose (MTD) or maximum administered dose (MAD). METHODS: We conducted a 3 + 3 dose-escalation trial in patients with recurrent, platinum-resistant EOC with RECIST v. 1.1 measurable disease and ≤4 prior chemotherapy regimens. Two dosing cohorts (2.5 mg/kg and 5 mg/kg) were targeted; however, an intermediate dose level (3.5 mg/kg) was to be evaluated if the 5 mg/kg dose was not tolerable. Demcizumab was administered on days 1 and 15 and paclitaxel, weekly on days 1, 8, and 15 for each of three 28-day cycles: the 3-cycle doublet could be repeated once if safe. Thereafter, paclitaxel was administered until unacceptable toxicity or disease progression. RESULTS: Nineteen patients were enrolled. No dose-limiting toxicities (DLT) were observed; however, the intermediate dose level (3.5 mg/kg) was enrolled and expanded based on emerging safety data from other trials in the demcizumab program. The MTD was not reached. The most common treatment emergent adverse events (TEAE) were diarrhea (68%), fatigue (58%), peripheral edema (53%), and nausea (53%). Pulmonary hypertension, grade 2 (n = 2) and grade 1 (n = 1), was observed. Overall response rate (ORR) was 21% (95% CI: 6-45%); clinical benefit rate (CBR) was 42% (95% CI: 20-66%). CONCLUSIONS: Demcizumab in combination with paclitaxel has a manageable toxicity profile and showed activity in patients with heavily pretreated platinum-resistant ovarian cancer.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Carcinoma Epitelial do Ovário/tratamento farmacológico , Neoplasias das Tubas Uterinas/tratamento farmacológico , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Peritoneais/tratamento farmacológico , Adulto , Idoso , Anticorpos Monoclonais Humanizados/administração & dosagem , Anticorpos Monoclonais Humanizados/efeitos adversos , Relação Dose-Resposta a Droga , Feminino , Humanos , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/tratamento farmacológico , Paclitaxel/administração & dosagem , Paclitaxel/efeitos adversos , Intervalo Livre de Progressão , Análise de SobrevidaRESUMO
Background: Cervical ectopic pregnancy is a rare condition, historically treated by hysterectomy. Case Report: A 33-year-old female at 13 weeks 3 days' gestation was diagnosed with a cervical ectopic pregnancy. She underwent a uterine artery embolization, fetal intrathoracic potassium chloride injection, amniocentesis, and ultrasound-guided suction dilation and curettage with the use of intracervical vasopressin, flowable gelatin with thrombin, and cervical cerclage. Conclusion: Advanced cervical ectopic pregnancy can be successfully managed in a conservative fashion in a patient who strongly desires future fertility.
RESUMO
Reliable approaches to predict residual disease prior to primary debulking surgery have been sought to further personalize surgical approaches. Reliance on molecular biomarkers alone in a complex clinical environment is challenging and algorithms that incorporate both molecular and clinical features may need to be considered.See related article by Heitz et al., p. 213.