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1.
Cancer Res Commun ; 2024 Jul 10.
Artículo en Inglés | MEDLINE | ID: mdl-38984891

RESUMEN

Chromobox 2 (CBX2), an epigenetic reader and component of Polycomb Repressor Complex 1 (PRC1), is highly expressed in >75% of high-grade serous carcinoma (HGSC). Increased CBX2 expression is associated with poorer survival, while CBX2 knockdown leads to improved chemotherapy sensitivity. In an HGSC immune competent murine model, knockdown of CBX2 decreased tumor progression. We sought to explore the impact of modulation of CBX2 on the tumor immune microenvironment (TIME), understanding that the TIME plays a critical role in disease progression and development of therapy resistance. Exploration of existing datasets demonstrated that elevated CBX2 expression significantly correlated with the specific immune cell types in the TIME. RNA-seq and pathway analysis of differentially expressed genes demonstrated immune signature enrichment. Confocal microscopy and co-culture experiments found modulation of CBX2 leads to increased recruitment and infiltration of macrophages. Flow cytometry of macrophages cultured with CBX2 overexpressing cells showed increased M2-like macrophages and decreased phagocytosis activity. Cbx2 knockdown in the Trp53, Brca2 null ID8 syngeneic murine model (ID8 Trp53-/- Brca2-/-) led to decreased tumor progression compared to control. NanoString Immuno-Oncology Panel analysis suggested knock down in Cbx2 shifts immune cell composition, with an increase in macrophages. Multispectral immunohistochemistry further confirmed an increase in macrophage infiltration. Increased CBX2 expression leads to recruitment and polarization of pro-tumor macrophages and targeting CBX2 may serve to modulate the TIME to enhance the efficacy of immune therapies.

2.
Cancer Res Commun ; 4(3): 822-833, 2024 Mar 18.
Artículo en Inglés | MEDLINE | ID: mdl-38451784

RESUMEN

High-grade serous carcinoma (HGSC) of the fallopian tube, ovary, and peritoneum is the most common type of ovarian cancer and is predicted to be immunogenic because the presence of tumor-infiltrating lymphocytes conveys a better prognosis. However, the efficacy of immunotherapies has been limited because of the immune-suppressed tumor microenvironment (TME). Tumor metabolism and immune-suppressive metabolites directly affect immune cell function through the depletion of nutrients and activation of immune-suppressive transcriptional programs. Tryptophan (TRP) catabolism is a contributor to HGSC disease progression. Two structurally distinct rate-limiting TRP catabolizing enzymes, indoleamine 2,3-dioxygenase 1 (IDO1) and tryptophan 2,3-dioxygenase 2 (TDO2), evolved separately to catabolize TRP. IDO1/TDO2 are aberrantly expressed in carcinomas and metabolize TRP into the immune-suppressive metabolite kynurenine (KYN), which can engage the aryl hydrocarbon receptor to drive immunosuppressive transcriptional programs. To date, IDO inhibitors tested in clinical trials have had limited efficacy, but those inhibitors did not target TDO2, and we find that HGSC cell lines and clinical outcomes are more dependent on TDO2 than IDO1. To identify inflammatory HGSC cancers with poor prognosis, we stratified patient ascites samples by IL6 status, which correlates with poor prognosis. Metabolomics revealed that IL6-high patient samples had enriched KYN. TDO2 knockdown significantly inhibited HGSC growth and TRP catabolism. The orally available dual IDO1/TDO2 inhibitor, AT-0174, significantly inhibited tumor progression, reduced tumor-associated macrophages, and reduced expression of immune-suppressive proteins on immune and tumor cells. These studies demonstrate the importance of TDO2 and the therapeutic potential of AT-0174 to overcome an immune-suppressed TME. SIGNIFICANCE: Developing strategies to improve response to chemotherapy is essential to extending disease-free intervals for patients with HGSC of the fallopian tube, ovary, and peritoneum. In this article, we demonstrate that targeting TRP catabolism, particularly with dual inhibition of TDO2 and IDO1, attenuates the immune-suppressive microenvironment and, when combined with chemotherapy, extends survival compared with chemotherapy alone.


Asunto(s)
Neoplasias Ováricas , Triptófano Oxigenasa , Femenino , Humanos , Triptófano Oxigenasa/genética , Triptófano/metabolismo , Antígeno B7-H1 , Interleucina-6 , Quinurenina/metabolismo , Neoplasias Ováricas/tratamiento farmacológico , Inhibidores Enzimáticos/farmacología , Macrófagos/metabolismo , Microambiente Tumoral
3.
Gynecol Oncol Rep ; 52: 101356, 2024 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-38523623

RESUMEN

Metastatic and recurrent cervical cancer is difficult to treat with limited options following platinum-based chemotherapy. Tisotumab vedotin (TV) is an antibody drug conjugate (ADC) targeted at a tissue factor (TF), which is a cell surface protein that is upregulated in the majority of cervical cancers. Prior clinical trials have demonstrated efficacy of TV in metastatic and recurrent cervical cancer with an objective response rate of 24-26 % with an 8.3 month duration of response. In this case series, we present 3 patients with recurrent or progressive cervical cancer of three different histologies (squamous cell, adenocarcinoma, and human papillomavirus (HPV)-independent gastric type carcinomas). We demonstrate a 100 % complete response rate with average time of complete response of 4.33 months. The duration of response was not reached as none of our patients had a confirmed progression at the time of writing this manuscript, but the mean time since the initiation of treatment was 6.1 months. In concordance with the clinical trials, our patients tolerated TV well although the grade 3 ocular toxicities were higher in our patients compared to prior data. This case series presents data confirming the efficacy and tolerability of TV in patients with recurrent cervical cancer, including an HPV-independent gastric type cervical cancer.

4.
bioRxiv ; 2024 Jan 29.
Artículo en Inglés | MEDLINE | ID: mdl-38352574

RESUMEN

Despite ovarian cancer being the deadliest gynecological malignancy, there has been little change to therapeutic options and mortality rates over the last three decades. Recent studies indicate that the composition of the tumor immune microenvironment (TIME) influences patient outcomes but are limited by a lack of spatial understanding. We performed multiplexed ion beam imaging (MIBI) on 83 human high-grade serous carcinoma tumors - one of the largest protein-based, spatially-intact, single-cell resolution tumor datasets assembled - and used statistical and machine learning approaches to connect features of the TIME spatial organization to patient outcomes. Along with traditional clinical/immunohistochemical attributes and indicators of TIME composition, we found that several features of TIME spatial organization had significant univariate correlations and/or high relative importance in high-dimensional predictive models. The top performing predictive model for patient progression-free survival (PFS) used a combination of TIME composition and spatial features. Results demonstrate the importance of spatial structure in understanding how the TIME contributes to treatment outcomes. Furthermore, the present study provides a generalizable roadmap for spatial analyses of the TIME in ovarian cancer research.

5.
Gynecol Oncol ; 177: 53-59, 2023 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-37639903

RESUMEN

OBJECTIVE: Genetic testing for ovarian cancer (OC) patients is essential to consideration of PARP inhibitor therapy. To improve access, we piloted a Genetic Testing Station (GTS) allowing patients to have a same-day genetic testing visit facilitated by Genetic Counselor Assistants (GCAs) under the supervision of Genetic Counselors (GCs). METHODS: The GTS was implemented December 2018 and operated through February 2020. Gynecologic Oncologists offered ovarian cancer patients a same-day GTS visit with a GCA. The patient received education via videos designed by GCs and then provided consent, a brief family history, and a sample for a standardized 133-gene panel. Results were provided by a GC. Patients were retrospectively identified by querying the medical record for OC patients seen 12 months prior to and 18 months after GTS implementation. RESULTS: A total of 482 patients pre-GTS were compared to 625 patients post-GTS. Genetic testing increased from 68.5% to 75.4% (p = 0.012) after implementation, primarily in patients with epithelial histologies (80% vs 89% in pre-GTS vs post-GTS, p = 0.005). Time from referral for genetic testing to obtaining results was evaluated in the post-GTS cohort, comparing patients who had traditional counseling to those who utilized the GTS. Time to obtaining results was 21 days in the GTS group (95% CI [10, 34]) compared to 56 days (95% CI [41,76]) in the traditional genetic counseling group. CONCLUSIONS: The GTS reduces barriers to care and facilitates discussion of precision treatment within a timely fashion while optimizing GC clinic time. Access improvement remains integral to improving uptake of genetic testing.

6.
Int J Gynecol Cancer ; 28(9): 1796-1804, 2018 11.
Artículo en Inglés | MEDLINE | ID: mdl-30371565

RESUMEN

OBJECTIVE: The aim of this study was to evaluate contemporary practices and opinions among gynecologic oncologists regarding the use of total pelvic exenteration (TPE) for palliative intent. METHODS: This cross-sectional study of the membership of the Society of Gynecologic Oncology utilized an electronic survey to assess the opinions and practice patterns of gynecologic oncologists regarding TPEs. The primary outcome was willingness to consider a TPE for palliative intent, and demographic and practice characteristics were collected for correlation. Qualitative data were also collected. Descriptive statistics are presented, and χ tests, Fisher exact tests, and logistic regression analyses were used. RESULTS: We included 315 surveys for analysis, for a completed response rate of 23.5%. Approximately half (52.4%, n = 165) of respondents indicated willingness to consider palliative TPE. When controlled for all variables, gynecologic oncologists who were more than 10 years out of fellowship were less likely to perform a palliative exenteration (odds ratio, 0.55; 95% confidence interval, 0.30-0.98), whereas those who reported experience with minimally invasive exenteration were more likely to offer it for palliation (odds ratio, 2.20; 95% confidence interval, 1.07-4.73). Fifty-three respondents (16.8%) provided qualitative data. The themes that emerged as considerations for TPE as palliation were (1) symptoms and quality of life, (2) surgical and perioperative morbidity, (3) anticipated overall survival, (4) counseling and informed consent, (5) functional status and comorbidities, (6) likelihood of residual disease, and (7) alternative procedures available for palliation. CONCLUSION: Half of gynecologic oncologists seem to be willing to offer a palliative TPE, although more-experienced gynecologic oncologists are more likely to reserve the procedure for curative intent.


Asunto(s)
Neoplasias Endometriales/cirugía , Adulto , Anciano , Anciano de 80 o más Años , Quimioterapia Adyuvante , Estudios Transversales , Supervivencia sin Enfermedad , Neoplasias Endometriales/tratamiento farmacológico , Neoplasias Endometriales/patología , Femenino , Adhesión a Directriz , Ginecología/métodos , Ginecología/normas , Humanos , Histerectomía , Escisión del Ganglio Linfático , Oncología Médica/métodos , Oncología Médica/normas , Persona de Mediana Edad , Estadificación de Neoplasias , Cuidados Paliativos , Exenteración Pélvica , Estudios Retrospectivos , Factores de Riesgo , Salpingooforectomía , Resultado del Tratamiento
7.
Cancer Immunol Res ; 3(11): 1257-68, 2015 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-26138335

RESUMEN

Immune checkpoint blockade has shown significant therapeutic efficacy in melanoma and other solid tumors, but results in ovarian cancer have been limited. With evidence that tumor immunogenicity modulates the response to checkpoint blockade, and data indicating that BRCA-deficient ovarian cancers express higher levels of immune response genes, we hypothesized that BRCA(-) ovarian tumors would be vulnerable to checkpoint blockade. To test this hypothesis, we used an immunocompetent BRCA1-deficient murine ovarian cancer model to compare treatment with CTLA-4 or PD-1/PD-L1 antibodies alone or combined with targeted cytotoxic therapy using a PARP inhibitor. Correlative studies were performed in vitro using human BRCA1(-) cells. We found that CTLA-4 antibody, but not PD-1/PD-L1 blockade, synergized therapeutically with the PARP inhibitor, resulting in immune-mediated tumor clearance and long-term survival in a majority of animals (P < 0.0001). The survival benefit of this combination was T-cell mediated and dependent on increases in local IFNγ production in the peritoneal tumor environment. Evidence of protective immune memory was observed more than 60 days after completion of therapy. Similar increases in the cytotoxic effect of PARP inhibition in the presence of elevated levels of IFNγ in human BRCA1(-) cancer cells support the translational potential of this treatment protocol. These results demonstrate that CTLA-4 blockade combined with PARP inhibition induces protective antitumor immunity and significant survival benefit in the BRCA1(-) tumor model, and support clinical testing of this regimen to improve outcomes for women with hereditary ovarian cancer.


Asunto(s)
Antineoplásicos/uso terapéutico , Antígeno CTLA-4/antagonistas & inhibidores , Neoplasias Ováricas/terapia , Inhibidores de Poli(ADP-Ribosa) Polimerasas/uso terapéutico , Ubiquitina-Proteína Ligasas/deficiencia , Animales , Anticuerpos Monoclonales/uso terapéutico , Antineoplásicos/administración & dosificación , Terapia Combinada , Citotoxicidad Inmunológica , Relación Dosis-Respuesta a Droga , Evaluación Preclínica de Medicamentos/métodos , Femenino , Humanos , Memoria Inmunológica , Inmunoterapia/métodos , Interferón gamma/biosíntesis , Interferón gamma/inmunología , Ratones Endogámicos C57BL , Trasplante de Neoplasias , Neoplasias Ováricas/inmunología , Neoplasias Ováricas/metabolismo , Neoplasias Ováricas/patología , Inhibidores de Poli(ADP-Ribosa) Polimerasas/administración & dosificación , Subgrupos de Linfocitos T/inmunología , Células Tumorales Cultivadas
8.
Mol Cancer Res ; 12(11): 1644-1654, 2014 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-25030371

RESUMEN

UNLABELLED: The role of 17ß-estradiol (E2) in breast cancer development and tumor growth has traditionally been attributed exclusively to the activation of estrogen receptor-α (ERα). Although targeted inhibition of ERα is a successful approach for patients with ERα(+) breast cancer, many patients fail to respond or become resistant to anti-estrogen therapy. The discovery of the G protein-coupled estrogen receptor (GPER) suggested an additional mechanism through which E2 could exert its effects in breast cancer. Studies have demonstrated clinical correlations between GPER expression in human breast tumor specimens and increased tumor size, distant metastasis, and recurrence, as well as established a proliferative role for GPER in vitro; however, direct in vivo evidence has been lacking. To this end, a GPER-null mutation [GPER knockout (KO)] was introduced, through interbreeding, into a widely used transgenic mouse model of mammary tumorigenesis [MMTV-PyMT (PyMT)]. Early tumor development, assessed by the extent of hyperplasia and proliferation, was not different between GPER wild-type/PyMT (WT/PyMT) and those mice harboring the GPER-null mutation (KO/PyMT). However, by 12 to 13 weeks of age, tumors from KO/PyMT mice were smaller with decreased proliferation compared with those from WT/PyMT mice. Furthermore, tumors from the KO/PyMT mice were of histologically lower grade compared with tumors from their WT counterparts, suggesting less aggressive tumors in the KO/PyMT mice. Finally, KO/PyMT mice displayed dramatically fewer lung metastases compared with WT/PyMT mice. Combined, these data provide the first in vivo evidence that GPER plays a critical role in breast tumor growth and distant metastasis. IMPLICATIONS: This is the first description of a role for the novel estrogen receptor GPER in breast tumorigenesis and metastasis, demonstrating that it represents a new target in breast cancer diagnosis, prognosis, and therapy.


Asunto(s)
Carcinogénesis/metabolismo , Carcinogénesis/patología , Neoplasias Pulmonares/secundario , Neoplasias Mamarias Animales/metabolismo , Neoplasias Mamarias Animales/patología , Receptores Acoplados a Proteínas G/metabolismo , Animales , Carcinogénesis/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Receptor alfa de Estrógeno/metabolismo , Estrógenos , Hiperplasia , Neoplasias Pulmonares/patología , Neoplasias Mamarias Animales/tratamiento farmacológico , Ratones Transgénicos , Ovariectomía , Pronóstico , Receptores de Estrógenos , Receptores Acoplados a Proteínas G/deficiencia , Tamoxifeno/farmacología , Tamoxifeno/uso terapéutico
9.
Circ Res ; 104(3): 288-91, 2009 Feb 13.
Artículo en Inglés | MEDLINE | ID: mdl-19179659

RESUMEN

We found that the selective stimulation of the intracellular, transmembrane G protein-coupled estrogen receptor (GPER), also known as GPR30, acutely lowers blood pressure after infusion in normotensive rats and dilates both rodent and human arterial blood vessels. Stimulation of GPER blocks vasoconstrictor-induced changes in intracellular calcium concentrations and vascular tone, as well as serum-stimulated cell proliferation of human vascular smooth muscle cells. Deletion of the GPER gene in mice abrogates vascular effects of GPER activation and is associated with visceral obesity. These findings suggest novel roles for GPER in protecting from cardiovascular disease and obesity.


Asunto(s)
Aterosclerosis/metabolismo , Presión Sanguínea/efectos de los fármacos , Obesidad/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Animales , Estradiol/farmacología , Femenino , Humanos , Masculino , Arterias Mamarias/efectos de los fármacos , Ratones , Ratones Mutantes , Ratas , Ratas Sprague-Dawley , Receptores de Estrógenos , Vasodilatación/efectos de los fármacos
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