Targeting tumor-associated macrophages (TAMs) is a promising strategy to modify the immunosuppressive tumor microenvironment and improve cancer immunotherapy. Monoamine oxidase A (MAO-A) is an enzyme ...best known for its function in the brain; small molecule MAO inhibitors (MAOIs) are clinically used for treating neurological disorders. Here we observe MAO-A induction in mouse and human TAMs. MAO-A-deficient mice exhibit decreased TAM immunosuppressive functions corresponding with enhanced antitumor immunity. MAOI treatment induces TAM reprogramming and suppresses tumor growth in preclinical mouse syngeneic and human xenograft tumor models. Combining MAOI and anti-PD-1 treatments results in synergistic tumor suppression. Clinical data correlation studies associate high intratumoral MAOA expression with poor patient survival in a broad range of cancers. We further demonstrate that MAO-A promotes TAM immunosuppressive polarization via upregulating oxidative stress. Together, these data identify MAO-A as a critical regulator of TAMs and support repurposing MAOIs for TAM reprogramming to improve cancer immunotherapy.
Tumor organoids maintain cell-cell interactions, heterogeneity, microenvironment, and drug response of the sample they originate from. Thus, there is increasing interest in developing tumor organoid ...models for drug development and personalized medicine applications. Although organoids are in principle amenable to high-throughput screenings, progress has been hampered by technical constraints and extensive manipulations required by current methods. Here we introduce a miniaturized method that uses a simplified geometry by seeding cells around the rim of the wells (mini-rings). This allows high-throughput screenings in a format compatible with automation as shown using four patient-derived tumor organoids established from two ovarian and one peritoneal high-grade serous carcinomas and one carcinosarcoma of the ovary. Using our automated screening platform, we identified personalized responses by measuring viability, number, and size of organoids after exposure to 240 kinase inhibitors. Results are available within a week from surgery, a timeline compatible with therapeutic decision-making.
The Polycomb group transcriptional repressor Bmi-1 is often upregulated in prostate cancer, but its functional roles in prostate stem cell maintenance and prostate cancer are unclear. Loss- and ...gain-of-function analysis in a prostate sphere assay indicates that Bmi-1 expression is required for self-renewal activity and maintenance of p63
+ stem cells. Loss of Bmi-1 blocks the self-renewal activity induced by heightened β-catenin signaling, suggesting that Bmi-1 is required for full activity of another self-renewal pathway. In vivo, Bmi-1 expression is necessary for normal prostate tubule regeneration. Altered self-renewal and proliferation through Bmi-1 modulation diminishes the susceptibility of prostate cells to transformation. In an in vivo prostate regeneration system, Bmi-1 inhibition protects prostate cells from FGF10-driven hyperplasia and slows the growth of aggressive Pten-deletion-induced prostate cancer. We conclude that Bmi-1 is a crucial regulator of self-renewal in adult prostate cells and plays important roles in prostate cancer initiation and progression.
► Bmi-1 regulates prostate stem cell maintenance and self-renewal in a sphere assay ► Bmi-1 loss reverses heightened self-renewal activity induced by β-catenin signaling ► Inhibition of Bmi-1 protects prostate cells from growth factor-induced hyperplasia ► Loss of Bmi-1 attenuates the formation of Pten-deletion-mediated prostate carcinoma
Prevailing theories suggest that luminal cells are the origin of prostate cancer because it is histologically defined by basal cell loss and malignant luminal cell expansion. We introduced a series ...of genetic alterations into prospectively identified populations of murine basal/stem and luminal cells in an in vivo prostate regeneration assay. Stromal induction of FGF signaling, increased expression of the ETS family transcription factor ERG1, and constitutive activation of PI3K signaling were evaluated. Combination of activated PI3K signaling and heightened androgen receptor signaling, which is associated with disease progression to androgen independence, was also performed. Even though luminal cells fail to respond, basal/stem cells demonstrate efficient capacity for cancer initiation and can produce luminal-like disease characteristic of human prostate cancer in multiple models. This finding provides evidence in support of basal epithelial stem cells as one target cell for prostate cancer initiation and demonstrates the propensity of primitive cells for tumorigenesis.
High-grade serous ovarian cancers (HGSOCs) likely consist of poorly differentiated stem-like cells (PDSLCs) and differentiated tumor cells. Conventional therapeutics are incapable of completely ...eradicating PDSLCs, contributing to disease progression and tumor relapse. Primary NK cells are known to effectively lyse PDSLCs, but they exhibit low or minimal cytotoxic potential against well-differentiated tumors. We have introduced and discussed the characteristics of super-charged NK (sNK) cells in this review. sNK cells, in comparison to primary NK cells, exhibit a significantly higher capability for the direct killing of both PDSLCs and well-differentiated tumors. In addition, sNK cells secrete significantly higher levels of cytokines, especially those known to induce the differentiation of tumors. In addition, we propose that a combination of sNK and chemotherapy could be one of the most effective strategies to eliminate the heterogeneous population of ovarian tumors; sNK cells can lyse both PDSLCs and well-differentiated tumors, induce the differentiation of PDSLCs, and could be used in combination with chemotherapy to target both well-differentiated and NK-induced differentiated tumors.
One of the major challenges in the treatment of cancer are differential responses of patients to existing standard of care anti-cancer drugs. These differential responses may, in part, be due to a ...diverse range of genomic, epigenomic, proteomic, and metabolic alterations among individuals suffering from the same type of cancer. Precision medicine is an emerging approach in cancer therapeutics that takes into account specific molecular alterations, environmental factors as well as lifestyle of individual patients. This approach allows clinicians and researchers to select or predict treatments that would most likely benefit the patient based on their individual tumor characteristics. One class of precision medicine tools are predictive, in vitro drug-response assays designed to test the sensitivity of patient tumor cells to existing or novel therapies. These assays have the potential to rapidly identify the most effective treatments for cancer patients and thus hold great promise in the field of precision medicine. In this review, we have highlighted several drug-response assays developed in ovarian cancer and discussed the current challenges and future prospects of these assays in the clinical management of this disease.
The expression of androgen receptor (AR) is not commonly tested or studied in uterine cancers, unlike estrogen receptor (ER) and progesterone receptor (PR) which are positive in most endometrial ...carcinomas. In this series, we evaluated the expression of AR and its comparison to ER and PR in different types of endometrial cancers and have reviewed the literature. The status of AR, ER, and PR expression were evaluated in 71 cases which were categorized into endometrial endometrioid cancer (EEC), non-endometrioid endometrial cancers (NEEC), and metastatic carcinomas of endometrium. Expression of the receptors were compared to each other as well as to mismatch repair proteins (MMR), p53, and body mass index (BMI) using Fisher's Exact test in the StatPlus software. In EECs, the positivity was 97% for all the three receptors. In NEEC, positivity rates were 68%, 48%, and 35% for AR, ER, and PR respectively. In Metastatic carcinomas, AR and ER positivity was seen in 100% while PR was positive in 75% of the cases. In all cancers, the rates were 17% (11/66) for MMR loss, 57% (30/53) for p53 aberrant expression, and 76% (54/71) for the patients with BMI of greater than or equal to 25 (kg/m2). AR is expressed in a high percentage of endometrial cancers. Its significance is more evident in high-grade NEEC where ER and PR may not be expressed. These findings warrant further evaluation of AR expression and candidacy of this pathway as a potential therapeutic target in endometrial cancers.
High-risk human papillomavirus (hrHPV) infection is a necessary risk factor for cervical and anal dysplasia. Over the last five years, there is increasing evidence that the natural history of ...hrHPV-induced anal cancer is close to that of cervical cancer. However, evidence-based anal cancer screening recommendations are limited and thus this study aims to characterize the prevalence of cervical dysplasia in women with anal dysplasia. In this study, we aimed to identify the association of anal dysplasia with cervical dysplasia and high-risk HPV subtypes in women.
A retrospective observational study was performed from January 2015 to December 2022 at an academic medical center. Women referred for anal cancer screening with Pap smears and anos-copies were evaluated for lifetime history of cervical dysplasia and
for correlation with hrHPV subtypes during screening. Multivariate logistic regression and chi-square tests were performed.
114 women who underwent anal cancer screening were identified. 78 (68.4%) patients were identified to have anal dysplasia and 16 (20.5%) had high-grade anal dysplasia. Cervical cancer screening data was identified for 109 women, of which 29 (26.6%) had cervical dysplasia, however none had high-grade cervical dysplasia. 50 (43.9%) women were positive for human immunodeficiency virus (HIV). Preliminary analyses show that those with anal dysplasia are more likely to have cervical dysplasia (OR 7.30, p=0.004). Those with cervical dysplasia are more like to have high-risk anal HPV (OR 4.72, p=0.005) and anal dysplasia (OR 7.18, p=0.004). Though those with high-grade anal cytology were not found to have cervical dysplasia, women with HIV were more likely to have cervical dysplasia with high-grade anal cytology (p=0.012).
We found that high-risk anal HPV and anal dysplasia were more likely to be found in those with cervical dysplasia. We also found that rates of anal and cervical dysplasia were increased in those with HIV and a history of any malignancy. Since anal dysplasia can be detected and subsequently treated, anal cancer screening should be recommended to women with cervical dysplasia. Further studies are warranted to guide recommendations to screen women with cervical dysplasia for anal dysplasia.
Primary vulvar and vaginal cancers are rare female genital tract malignancies which are staged using the 2009 International Federation of Gynecology and Obstetrics (FIGO) staging. These cancers ...account for approximately 2,700 deaths annually in the USA. The most common histologic subtype of both vulvar and vaginal cancers is squamous cell carcinoma, with an increasing role of the human papillomavirus (HPV) in a significant number of these tumors. Lymph node involvement is the hallmark of FIGO stage 3 vulvar cancer while pelvic sidewall involvement is the hallmark of FIGO stage 3 vaginal cancer. Imaging techniques include computed tomography (CT), positron emission tomography (PET)-CT, magnetic resonance imaging (MRI), and PET-MRI. MRI is the imaging modality of choice for preoperative clinical staging of nodal and metastatic involvement while PET-CT is helpful with assessing response to neoadjuvant treatment and for guiding patient management. Determining the pretreatment extent of disease has become more important due to modern tailored operative approaches and use of neoadjuvant chemoradiation therapy to reduce surgical morbidity. Moreover, imaging is used to determine the full extent of disease for radiation planning and for evaluating treatment response. Understanding the relevant anatomy of the vulva and vaginal regions and the associated lymphatic pathways is helpful to recognize the potential routes of spread and to correctly identify the appropriate FIGO stage. The purpose of this article is to review the clinical features, pathology, and current treatment strategies for vulvar and vaginal malignancies and to identify multimodality diagnostic imaging features of these gynecologic cancers, in conjunction with its respective 2009 FIGO staging system guidelines.
Ovarian malignancies are a leading cause of cancer-related death for US women. High-grade serous ovarian carcinomas (HGSOCs), the most common ovarian cancer subtype, are aggressive tumors with poor ...outcomes. Mutations in TP53 are common in HGSOCs, with a subset resulting in p53 aggregation and misregulation. ReACp53 is a peptide designed to inhibit mutant p53 aggregation and has been shown efficacious in targeting cancer cells in vitro and in vivo. As p53 regulates apoptosis, combining ReACp53 with carboplatin represents a logical therapeutic strategy. The efficacy of this combinatorial approach was tested in eight ovarian cancer cell lines and 10 patient HGSOC samples using an in vitro organoid drug assay, with the SynergyFinder tool utilized for calculating drug interactions. Results demonstrate that the addition of ReACp53 to carboplatin enhanced tumor cell targeting in the majority of samples tested, with synergistic effects measured in 2 samples, additivity measured in 14 samples, and antagonism measured in 1 sample. This combination was found to be synergistic in OVCAR3 ovarian cancer cells in vitro through enhanced apoptosis, and survival of mice bearing OVCAR3 intraperitoneal xenografts was extended when treated with the addition of ReACp53 to carboplatin versus carboplatin alone. Results suggest that carboplatin and ReACp53 may be a potential strategy in targeting a subset of HGSOCs.
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