Publications by authors named "Anil K Sood"

642 Publications

Clinically translatable quantitative molecular photoacoustic imaging with liposome-encapsulated ICG J-aggregates.

Nat Commun 2021 Sep 13;12(1):5410. Epub 2021 Sep 13.

Department of Imaging Physics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.

Photoacoustic (PA) imaging is a functional and molecular imaging technique capable of high sensitivity and spatiotemporal resolution at depth. Widespread use of PA imaging, however, is limited by currently available contrast agents, which either lack PA-signal-generation ability for deep imaging or their absorbance spectra overlap with hemoglobin, reducing sensitivity. Here we report on a PA contrast agent based on targeted liposomes loaded with J-aggregated indocyanine green (ICG) dye (i.e., PAtrace) that we synthesized, bioconjugated, and characterized to addresses these limitations. We then validated PAtrace in phantom, in vitro, and in vivo PA imaging environments for both spectral unmixing accuracy and targeting efficacy in a folate receptor alpha-positive ovarian cancer model. These study results show that PAtrace concurrently provides significantly improved contrast-agent quantification/sensitivity and SO estimation accuracy compared to monomeric ICG. PAtrace's performance attributes and composition of FDA-approved components make it a promising agent for future clinical molecular PA imaging.
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http://dx.doi.org/10.1038/s41467-021-25452-3DOI Listing
September 2021

Phase 1b dose expansion and translational analyses of olaparib in combination with capivasertib in recurrent endometrial, triple negative breast, and ovarian cancer.

Clin Cancer Res 2021 Sep 13. Epub 2021 Sep 13.

OHSU Knight Cancer Institute.

Purpose: Based on strong preclinical rationale, we sought to confirm recommended phase 2 dose for olaparib, a PARP inhibitor, combined with the AKT inhibitor capivasertib and assess molecular markers of response and resistance.

Experimental Design: We performed a safety lead in followed by expansion in endometrial, triple negative breast, or ovarian cancers. Olaparib 300mg orally twice daily (BID) and capivasertib orally BID on a four day on three day off schedule was evaluated. Two dose levels (DL) of capivasertib were planned: 400mg (DL1); 320mg (DL-1). Patients underwent biopsies at baseline and 28 days.

Results: 38 patients were enrolled. 7 (18%) had germline BRCA1/2 mutations. The first two patients on DL1 experienced dose limiting toxicities (DLTs) of diarrhea and vomiting. No DLTs were observed on DL-1 (n=6), therefore, DL1 was re-explored (n=6) with no DLTs, confirming DL1 as RP2D. Most common treatment-related grade 3/4 adverse events were anemia (23.7%) and leukopenia (10.5%). Of 32 evaluable subjects, 6 (19%) had partial response (PR); PR rate was 44.4% in endometrial cancer. Seven (22%) additional patients had stable disease greater than 4 months. Tumor analysis demonstrated strong correlations between response and immune activity, cell cycle alterations and DNA damage response. Therapy resistance was associated with receptor tyrosine kinase and RAS-MAPK pathway activity, metabolism and epigenetics.

Conclusions: Combination of olaparib and capivasertib is associated to no serious adverse events and demonstrates durable activity in ovarian, endometrial and breast cancers, with promising responses in endometrial cancer. Importantly, tumor samples acquired pre- and on-therapy can help predict patient benefit.
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http://dx.doi.org/10.1158/1078-0432.CCR-21-1656DOI Listing
September 2021

Immune microenvironment composition in high-grade serous ovarian cancers based on BRCA mutational status.

J Cancer Res Clin Oncol 2021 Sep 2. Epub 2021 Sep 2.

Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX, 77054, USA.

Purpose: An in-depth analysis of the tumor microenvironment of ovarian cancer is needed. The purpose of this study was to elucidate the architecture of the immune microenvironment of high-grade serous ovarian cancers (HGSCs) with or without BRCA1 and BRCA2 mutations.

Methods: A cohort of highly annotated HGSC patients with known germline BRCA1 and BRCA2 status was selected, and pretreatment tumor tissue specimens were analyzed with a multiplexed staining technique aimed at detecting lymphocytes, macrophages, and fibroblasts in the whole tumor area and in specific regions including epithelium, stroma, and perivascular areas.

Results: BRCA1- or BRCA2-mutated tumors showed a more immunogenic microenvironment, characterized by a higher abundance of CD8 and PD-L1 cells, than did tumors with wild-type BRCA1 and BRCA2. High numbers of PD-L1 and PD-L1CD8 cells were prognostic for event-free survival (hazard ratio [HR]: 0.41, 95% CI 0.21-0.79, p = 0.008 and HR 0.49, 95% CI 0.26-0.91, p = 0.025, respectively), as were high numbers of epithelial PD-L1 and FAPPD-L1 cells (HR 0.52, 95% CI 0.28-0.96, p = 0.037 and HR 0.27, 95% CI 0.08-0.87, p = 0.029) and CD8 cells (HR 0.51, 95% CI 0.28-0.93, p = 0.027).

Conclusions: This study reveals substantial differences between the immune microenvironment composition of germline BRCA-mutated and BRCA wild-type HGSC.
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http://dx.doi.org/10.1007/s00432-021-03778-1DOI Listing
September 2021

Assessment of In Vivo siRNA Delivery in Cancer Mouse Models.

Methods Mol Biol 2021 ;2372:157-168

Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center (MDACC), Houston, TX, USA.

RNA interference (RNAi) has rapidly become a powerful tool for target discovery and therapeutics. Small interfering RNAs (siRNAs) are highly effective in mediating sequence-specific gene silencing. However, the major obstacle for using siRNAs for cancer therapeutics is their systemic delivery from the administration site to target cells in vivo. This chapter describes approaches to deliver siRNA effectively for cancer treatment and discusses in detail the current methods to assess pharmacokinetics and biodistribution of siRNAs in vivo.
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http://dx.doi.org/10.1007/978-1-0716-1697-0_14DOI Listing
January 2021

CD63-mediated cloaking of VEGF in small extracellular vesicles contributes to anti-VEGF therapy resistance.

Cell Rep 2021 Aug;36(7):109549

Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Center for RNA Interference and Non-Coding RNA, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. Electronic address:

Despite wide use of anti-vascular endothelial growth factor (VEGF) therapy for many solid cancers, most individuals become resistant to this therapy, leading to disease progression. Therefore, new biomarkers and strategies for blocking adaptive resistance of cancer to anti-VEGF therapy are needed. As described here, we demonstrate that cancer-derived small extracellular vesicles package increasing quantities of VEGF and other factors in response to anti-VEGF therapy. The packaging process of VEGF into small extracellular vesicles (EVs) is mediated by the tetraspanin CD63. Furthermore, small EV-VEGF (eVEGF) is not accessible to anti-VEGF antibodies and can trigger intracrine VEGF signaling in endothelial cells. eVEGF promotes angiogenesis and enhances tumor growth despite bevacizumab treatment. These data demonstrate a mechanism where VEGF is partitioned into small EVs and promotes tumor angiogenesis and progression. These findings have clinical implications for biomarkers and therapeutic strategies for ovarian cancer.
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http://dx.doi.org/10.1016/j.celrep.2021.109549DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8422976PMC
August 2021

Rural residence is related to shorter survival in epithelial ovarian cancer patients.

Gynecol Oncol 2021 Aug 13. Epub 2021 Aug 13.

Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Washington University School of Medicine, St. Louis, MO, USA.

Objective: Rural residence has been related to health disparities and greater mortality risk in cancer patients, including gynecologic cancer patients. Lower survival rates for rural cancer survivors have been attributed to limited access to specialized healthcare, including surgery. Here, we examined whether a rural/urban survival gap existed in ovarian cancer patients receiving surgery at tertiary-care facilities, and potential causes for this gap, including educational attainment.

Methods: Rural and urban patients with high grade invasive ovarian cancer (n = 342) seeking treatment at two midwestern tertiary-care university hospitals were recruited pre-surgery and followed until death or censoring date. Rural/urban residence was categorized using the USDA Rural-Urban Continuum Codes. Stratified Cox proportional hazards regression analyses, with clinical site as strata, adjusting for clinical and demographic covariates, were used to examine the effect of rurality on survival.

Results: Despite specialized surgical care, rural cancer survivors showed a higher likelihood of death compared to their urban counterparts, HR = 1.39 (95% CI: 1.04, 1.85) p = 0.026, adjusted for covariates. A rurality by education interaction was observed (p = 0.027), indicating significantly poorer survival in rural vs. urban patients among those with trade school/some college education, adjusted HR = 2.49 (95% CI: 1.44, 4.30), p = 0.001; there was no rurality survival disparity for the other 2 levels of education.

Conclusions: Differences in ovarian cancer survival are impacted by rurality, which is moderated by educational attainment even in patients receiving initial care in tertiary settings. Clinicians should be aware of rurality and education as potential risk factors for adverse outcomes and develop approaches to address these possible risks.
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http://dx.doi.org/10.1016/j.ygyno.2021.07.035DOI Listing
August 2021

MEK inhibition overcomes resistance to EphA2-targeted therapy in uterine cancer.

Gynecol Oncol 2021 Aug 11. Epub 2021 Aug 11.

Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, United States of America; Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States of America; Center for RNA Interference and Non-Coding RNAs, The University of Texas MD Anderson Cancer Center, Houston, TX, United States of America. Electronic address:

Background: Our pilot clinical study of EphA2 inhibitor (dasatinib) plus paclitaxel and carboplatin showed interesting clinical activity in endometrial cancer with manageable toxicity. However, the underlying mechanisms of dasatinib resistance in uterine cancer are unknown. Here, we investigated potential mechanisms underlying resistance to EphA2 inhibitors in uterine cancer and examined the anti-tumor activity of EphA2 inhibitors alone and in combination with a MEK inhibitor.

Methods: We evaluated the antitumor activity of EphA2 inhibitors plus a MEK inhibitor using in vitro and in vivo orthotopic models of uterine cancer.

Results: EphA2 inhibitor induced MAPK in dasatinib-resistant uterine cancer cells (HEC-1A and Ishikawa) and BRAF/CRAF heterodimerization in HEC-1A cells. EphA2 inhibitor and trametinib significantly increased apoptosis in cancer cells resistant to EphA2 inhibitors compared with controls (p < 0.01). An in vivo study with the orthotopic HEC-1A model showed significantly greater antitumor response to combination treatment compared with dasatinib alone (p < 0.01). Combination treatment increased EphrinA1 and BIM along with decreased pMAPK, Jagged 1, and c-MYC expression in dasatinib-resistant cells. In addition, Spearman analysis using the TCGA data revealed that upregulation of EphA2 was significantly correlated with JAG1, MYC, NOTCH1, NOTCH3 and HES1 expression (p < 0.001, r = 0.25-0.43). Specifically, MAP3K15 and the NOTCH family genes were significantly related to poor clinical outcome in patients with uterine cancer.

Conclusions: These findings indicate that the MAPK pathway is activated in dasatinib-resistant uterine cancer cells and that EphrinA1-mediated MEK inhibition overcomes dasatinib resistance. Dual targeting of both EphA2 and MEK, combined with chemotherapy, should be considered for future clinical development.
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http://dx.doi.org/10.1016/j.ygyno.2021.08.003DOI Listing
August 2021

The Provocative Roles of Platelets in Liver Disease and Cancer.

Front Oncol 2021 21;11:643815. Epub 2021 Jul 21.

Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States.

Both platelets and the liver play important roles in the processes of coagulation and innate immunity. Platelet responses at the site of an injury are rapid; their immediate activation and structural changes minimize the loss of blood. The majority of coagulation proteins are produced by the liver-a multifunctional organ that also plays a critical role in many processes: removal of toxins and metabolism of fats, proteins, carbohydrates, and drugs. Chronic inflammation, trauma, or other causes of irreversible damage to the liver can dysregulate these pathways leading to organ and systemic abnormalities. In some cases, platelet-to-lymphocyte ratios can also be a predictor of disease outcome. An example is cirrhosis, which increases the risk of bleeding and prothrombotic events followed by activation of platelets. Along with a triggered coagulation cascade, the platelets increase the risk of pro-thrombotic events and contribute to cancer progression and metastasis. This progression and the resulting tissue destruction is physiologically comparable to a persistent, chronic wound. Various cancers, including colorectal cancer, have been associated with increased thrombocytosis, platelet activation, platelet-storage granule release, and thrombosis; anti-platelet agents can reduce cancer risk and progression. However, in cancer patients with pre-existing liver disease who are undergoing chemotherapy, the risk of thrombotic events becomes challenging to manage due to their inherent risk for bleeding. Chemotherapy, also known to induce damage to the liver, further increases the frequency of thrombotic events. Depending on individual patient risks, these factors acting together can disrupt the fragile balance between pro- and anti-coagulant processes, heightening liver thrombogenesis, and possibly providing a niche for circulating tumor cells to adhere to-thus promoting both liver metastasis and cancer-cell survival following treatment (that is, with minimal residual disease in the liver).
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http://dx.doi.org/10.3389/fonc.2021.643815DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8335590PMC
July 2021

Gene Body Methylation of the Lymphocyte-Specific Gene Results in Its Overexpression and Regulates Cancer mTOR Signaling.

Mol Cancer Res 2021 Aug 4. Epub 2021 Aug 4.

Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas.

Investigations into the function of nonpromoter DNA methylation have yielded new insights into epigenetic regulation of gene expression. Previous studies have highlighted the importance of distinguishing between DNA methylation in discrete functional regions; however, integrated nonpromoter DNA methylation and gene expression analyses across a wide number of tumor types and corresponding normal tissues have not been performed. Through integrated analysis of gene expression and DNA methylation profiles, we examined 32 tumor types and identified 57 tumor suppressors and oncogenes out of 260 genes exhibiting a correlation of > 0.5 between gene body methylation and gene expression in at least one tumor type. The lymphocyte-specific gene exhibits robust association between gene body methylation and expression across 19 of 32 tumor types examined. It is significantly overexpressed in kidney renal cell carcinoma (KIRC) and lung adenocarcinoma (LUAD) tumor tissues in comparison with respective control samples; and is significantly associated with lower overall survival in KIRC. Contrary to its canonical function in lymphocyte NFκB activation, CARD11 activates the mTOR pathway in KIRC and LUAD, resulting in suppressed autophagy. Furthermore, demethylation of a CpG island within the gene body of decreases gene expression. Collectively, our study highlights how DNA methylation outside the promoter region can impact tumor progression. IMPLICATIONS: Our study describes a novel regulatory role of gene body DNA methylation-dependent expression on mTOR signaling and its impact on tumor progression.
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http://dx.doi.org/10.1158/1541-7786.MCR-20-0753DOI Listing
August 2021

Human tumor microenvironment chip evaluates the consequences of platelet extravasation and combinatorial antitumor-antiplatelet therapy in ovarian cancer.

Sci Adv 2021 Jul 21;7(30). Epub 2021 Jul 21.

Department of Biomedical Engineering, College of Engineering, Texas A&M University, College Station, TX 77840, USA.

Platelets extravasate from the circulation into tumor microenvironment, enable metastasis, and confer resistance to chemotherapy in several cancers. Therefore, arresting tumor-platelet cross-talk with effective and atoxic antiplatelet agents in combination with anticancer drugs may serve as an effective cancer treatment strategy. To test this concept, we create an ovarian tumor microenvironment chip (OTME-Chip) that consists of a platelet-perfused tumor microenvironment and which recapitulates platelet extravasation and its consequences. By including gene-edited tumors and RNA sequencing, this organ-on-chip revealed that platelets and tumors interact through glycoprotein VI (GPVI) and tumor galectin-3 under shear. Last, as proof of principle of a clinical trial, we showed that a GPVI inhibitor, Revacept, impairs metastatic potential and improves chemotherapy. Since GPVI is an antithrombotic target that does not impair hemostasis, it represents a safe cancer therapeutic. We propose that OTME-Chip could be deployed to study other vascular and hematological targets in cancer.
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http://dx.doi.org/10.1126/sciadv.abg5283DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8294767PMC
July 2021

Extensive three-dimensional intratumor proteomic heterogeneity revealed by multiregion sampling in high-grade serous ovarian tumor specimens.

iScience 2021 Jul 21;24(7):102757. Epub 2021 Jun 21.

Women's Health Integrated Research Center, Inova Women's Service Line, Inova Health System, 3289 Woodburn Road, Annandale, VA 22042, USA.

Enriched tumor epithelium, tumor-associated stroma, and whole tissue were collected by laser microdissection from thin sections across spatially separated levels of ten high-grade serous ovarian carcinomas (HGSOCs) and analyzed by mass spectrometry, reverse phase protein arrays, and RNA sequencing. Unsupervised analyses of protein abundance data revealed independent clustering of an enriched stroma and enriched tumor epithelium, with whole tumor tissue clustering driven by overall tumor "purity." Comparing these data to previously defined prognostic HGSOC molecular subtypes revealed protein and transcript expression from tumor epithelium correlated with the differentiated subtype, whereas stromal proteins (and transcripts) correlated with the mesenchymal subtype. Protein and transcript abundance in the tumor epithelium and stroma exhibited decreased correlation in samples collected just hundreds of microns apart. These data reveal substantial tumor microenvironment protein heterogeneity that directly bears on prognostic signatures, biomarker discovery, and cancer pathophysiology and underscore the need to enrich cellular subpopulations for expression profiling.
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http://dx.doi.org/10.1016/j.isci.2021.102757DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8264160PMC
July 2021

Rationale for combination PARP inhibitor and antiangiogenic treatment in advanced epithelial ovarian cancer: A review.

Gynecol Oncol 2021 Aug 3;162(2):482-495. Epub 2021 Jun 3.

Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, United States.

Inhibitors of poly(ADP-ribose) polymerase (PARP) and angiogenesis have demonstrated single-agent activity in women with advanced ovarian cancer. Recent studies have aimed to establish whether combination therapy can augment the response seen with PARP inhibitors or antiangiogenic agents alone. This review provides an overview of PARP inhibitors and antiangiogenics as monotherapy in women with advanced ovarian cancer, explores potential mechanisms of action of PARP inhibitor and antiangiogenic combination treatments, reviews efficacy and safety data from trials evaluating this combination, and outlines ongoing and future trials evaluating this combination, discussing these in the context of the current and future treatment landscape for women with advanced ovarian cancer. Sentinel studies evaluating PARP inhibitor (n = 8), antiangiogenic (n = 4), and combination (n = 7) therapy were identified in women with newly diagnosed (n = 7) and recurrent (n = 12) ovarian cancer. PARP inhibitors included olaparib (n = 9), niraparib (n = 4), rucaparib (n = 1), and veliparib (n = 1). Antiangiogenic agents included bevacizumab (n = 7) and cediranib (n = 4). PARP inhibitors combined with antiangiogenics demonstrated efficacy based on objective response rates and progression-free survival (PFS) in the relapsed disease setting. Maintenance therapy with the PARP inhibitor, olaparib, plus antiangiogenic therapy offered a significant PFS benefit versus the antiangiogenic alone in women with newly diagnosed advanced ovarian cancer who tested positive for homologous recombination deficiency. Combination therapy was tolerated, with no new safety signals reported compared with monotherapy trials. PARP inhibitors and antiangiogenics have changed the landscape of ovarian cancer treatment. The PARP inhibitor plus antiangiogenic combination is a novel treatment option that appears promising in the first-line advanced and recurrent ovarian cancer settings, although the role of this combination in recurrent disease requires further elucidation. Defining which patients are candidates for monotherapy or combination therapy is critical, taking into consideration safety profiles of therapies alone or in combination, and how these treatments should be sequenced in clinical practice.
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http://dx.doi.org/10.1016/j.ygyno.2021.05.018DOI Listing
August 2021

Positive Psychosocial Factors and Oxytocin in the Ovarian Tumor Microenvironment.

Psychosom Med 2021 Jun;83(5):417-422

From the Department of Psychological and Brain Sciences (Cuneo, Schrepf, Lutgendorf), University of Iowa, Iowa City, Iowa; Department of Psychology (Szeto, McCabe), University of Miami, Coral Gables, Florida; Division of Gynecologic Oncology, Department of Obstetrics and Gynecology (Thaker), Washington University School of Medicine, St Louis, Missouri; Holden Comprehensive Cancer Center (Goodheart, Lutgendorf) and Division of Gynecologic Oncology, Department of Obstetrics and Gynecology (Goodheart, Lutgendorf), University of Iowa, Iowa City, Iowa; Department of Medicine, Division of Hematology/Oncology and Molecular Biology Institute, David Geffen School of Medicine (Cole), University of California, Los Angeles; Departments of Gynecologic Oncology, Cancer Biology and Center for RNA Interference and Noncoding RNA (Sood), University of Texas MD Anderson Cancer Center, Houston, Texas; and Diabetes Research Institute, Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, Miller School of Medicine (Mendez), University of Miami, Coral Gables, Florida.

Objective: Clinical ovarian cancer research shows relationships between psychosocial factors and disease-promoting aspects of the stress response (e.g., norepinephrine and cortisol). However, little is known about how psychosocial factors might relate to beneficial hormones in the ovarian tumor microenvironment. Here we examine relationships between psychosocial factors and tumor-associated oxytocin, a hormone linked to survival and antitumor processes in ovarian cancer.

Methods: Patients with ovarian cancer (n = 96) completed assessments of positive psychosocial factors (social support, positive affect, and purpose in life) and distress (perceived stress and depression) at the time of surgery. Levels of oxytocin and interleukin (IL) 6 in ascites fluid were obtained during surgery and analyzed by enzyme-linked immunosorbent assay. Multiple regression analyses adjusting a priori for patient age and disease stage examined associations between psychosocial factors and ascites oxytocin. IL-6 was used as a covariate in secondary analyses to examine the potentially confounding effects of inflammation in these relationships.

Results: Higher levels of positive affect (β = 0.22, p = .034), purpose in life (β = 0.31, p = .021), and social nurturance (β = 0.24, p = .024) were all related to higher levels of tumor-associated oxytocin at the time of surgery. In contrast, we found no effects for distress or social attachment. Relationships between oxytocin, purpose in life, and social nurturance were independent of IL-6, whereas positive affect was no longer significant with IL-6 in the model.

Conclusions: Tumor-associated oxytocin may be a previously uninvestigated link in the relationship between psychosocial factors and health in ovarian cancer. Future studies should examine causal mechanisms of relationships observed in this study.
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http://dx.doi.org/10.1097/PSY.0000000000000935DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8175871PMC
June 2021

Mitochondria in epithelial ovarian carcinoma exhibit abnormal phenotypes and blunted associations with biobehavioral factors.

Sci Rep 2021 Jun 2;11(1):11595. Epub 2021 Jun 2.

Division of Behavioral Medicine, Department of Psychiatry, Columbia University Irving Medical Center, New York, NY, USA.

Malignant tumor cells exhibit mitochondrial alterations and are also influenced by biobehavioral processes, but the intersection of biobehavioral factors and mitochondria in malignant tumors remains unexplored. Here we examined multiple biochemical and molecular markers of mitochondrial content and function in benign tissue and in high-grade epithelial ovarian carcinoma (EOC) in parallel with exploratory analyses of biobehavioral factors. First, analysis of a publicly-available database (n = 1435) showed that gene expression of specific mitochondrial proteins in EOC is associated with survival. Quantifying multiple biochemical and molecular markers of mitochondrial content and function in tissue from 51 patients with benign ovarian masses and 128 patients with high-grade EOC revealed that compared to benign tissue, EOCs exhibit 3.3-8.4-fold higher mitochondrial content and respiratory chain enzymatic activities (P < 0.001) but similar mitochondrial DNA (mtDNA) levels (- 3.1%), documenting abnormal mitochondrial phenotypes in EOC. Mitochondrial respiratory chain activity was also associated with interleukin-6 (IL-6) levels in ascites. In benign tissue, negative biobehavioral factors were inversely correlated with mitochondrial content and respiratory chain activities, whereas positive biobehavioral factors tended to be positively correlated with mitochondrial measures, although effect sizes were small to medium (r = - 0.43 to 0.47). In contrast, serous EOCs showed less pronounced biobehavioral-mitochondrial correlations. These results document abnormal mitochondrial functional phenotypes in EOC and warrant further research on the link between biobehavioral factors and mitochondria in cancer.
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http://dx.doi.org/10.1038/s41598-021-89934-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8172869PMC
June 2021

Inactivating Mutations of the Gene Weaken Ku80/Ku70-Mediated DNA Repair and Sensitize Endometrial Cancer to Chemotherapy.

Cancers (Basel) 2021 May 20;13(10). Epub 2021 May 20.

Department of Cancer Biology, Wake Forest Baptist Comprehensive Cancer Center, Winston-Salem, NC 27157, USA.

IK is a mitotic factor that promotes cell cycle progression. Our previous investigation of 271 endometrial cancer (EC) samples from the Cancer Genome Atlas (TCGA) dataset showed IK somatic mutations were enriched in a cluster of patients with high-grade and high-stage cancers, and this group had longer survival. This study provides insight into how IK somatic mutations contribute to EC pathophysiology. We analyzed the somatic mutational landscape of IK gene in 547 EC patients using expanded TCGA dataset. Co-immunoprecipitation and mass spectrometry were used to identify protein interactions. In vitro and in vivo experiments were used to evaluate IK's role in EC. The patients with IK-inactivating mutations had longer survival during 10-year follow-up. Frameshift and stop-gain were common mutations and were associated with decreased IK expression. IK knockdown led to enrichment of G2/M phase cells, inactivation of DNA repair signaling mediated by heterodimerization of Ku80 and Ku70, and sensitization of EC cells to cisplatin treatment. IK/Ku80 mutations were accompanied by higher mutation rates and associated with significantly better overall survival. Inactivating mutations of IK gene and loss of IK protein expression were associated with weakened Ku80/Ku70-mediated DNA repair, increased mutation burden, and better response to chemotherapy in patients with EC.
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http://dx.doi.org/10.3390/cancers13102487DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8160817PMC
May 2021

Joint IARC/NCI International Cancer Seminar Series Report: expert consensus on future directions for ovarian carcinoma research.

Carcinogenesis 2021 Jun;42(6):785-793

Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, DHHS, Bethesda, MD, USA.

Recently, ovarian cancer research has evolved considerably because of the emerging recognition that rather than a single disease, ovarian carcinomas comprise several different histotypes that vary by etiologic origin, risk factors, molecular profiles, therapeutic approaches and clinical outcome. Despite significant progress in our understanding of the etiologic heterogeneity of ovarian cancer, as well as important clinical advances, it remains the eighth most frequently diagnosed cancer in women worldwide and the most fatal gynecologic cancer. The International Agency for Research on Cancer and the United States National Cancer Institute jointly convened an expert panel on ovarian carcinoma to develop consensus research priorities based on evolving scientific discoveries. Expertise ranged from etiology, prevention, early detection, pathology, model systems, molecular characterization and treatment/clinical management. This report summarizes the current state of knowledge and highlights expert consensus on future directions to continue advancing etiologic, epidemiologic and prognostic research on ovarian carcinoma.
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http://dx.doi.org/10.1093/carcin/bgab043DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8427725PMC
June 2021

Conversion of RNA Aptamer into Modified DNA Aptamers Provides for Prolonged Stability and Enhanced Antitumor Activity.

J Am Chem Soc 2021 May 14;143(20):7655-7670. Epub 2021 May 14.

Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, United States.

Aptamers, synthetic single-strand oligonucleotides that are similar in function to antibodies, are promising as therapeutics because of their minimal side effects. However, the stability and bioavailability of the aptamers pose a challenge. We developed aptamers converted from RNA aptamer to modified DNA aptamers that target phospho-AXL with improved stability and bioavailability. On the basis of the comparative analysis of a library of 17 converted modified DNA aptamers, we selected aptamer candidates, GLB-G25 and GLB-A04, that exhibited the highest bioavailability, stability, and robust antitumor effect in experiments. Backbone modifications such as thiophosphate or dithiophosphate and a covalent modification of the 5'-end of the aptamer with polyethylene glycol optimized the pharmacokinetic properties, improved the stability of the aptamers by reducing nuclease hydrolysis and renal clearance, and achieved high and sustained inhibition of AXL at a very low dose. Treatment with these modified aptamers in ovarian cancer orthotopic mouse models significantly reduced tumor growth and the number of metastases. This effective silencing of the phospho-AXL target thus demonstrated that aptamer specificity and bioavailability can be improved by the chemical modification of existing aptamers for phospho-AXL. These results lay the foundation for the translation of these aptamer candidates and companion biomarkers to the clinic.
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http://dx.doi.org/10.1021/jacs.9b10460DOI Listing
May 2021

Combined VEGFR and MAPK pathway inhibition in angiosarcoma.

Sci Rep 2021 04 30;11(1):9362. Epub 2021 Apr 30.

Department of Gynecologic Oncology and Reproductive Medicine and Center for RNA Interference and Non-Coding RNA, UT MD Anderson Cancer Center, Houston, USA.

Angiosarcoma is an aggressive malignancy of endothelial cells that carries a high mortality rate. Cytotoxic chemotherapy can elicit clinical responses, but the duration of response is limited. Sequencing reveals multiple mutations in angiogenesis pathways in angiosarcomas, particularly in vascular endothelial growth factor (VEGFR) and mitogen-activated protein kinase (MAPK) signaling. We aimed to determine the biological relevance of these pathways in angiosarcoma. Tissue microarray consisting of clinical formalin-fixed paraffin embedded tissue archival samples were stained for phospho- extracellular signal-regulated kinase (p-ERK) with immunohistochemistry. Angiosarcoma cell lines were treated with the mitogen-activated protein kinase kinase (MEK) inhibitor trametinib, pan-VEGFR inhibitor cediranib, or combined trametinib and cediranib and viability was assessed. Reverse phase protein array (RPPA) was performed to assess multiple oncogenic protein pathways. SVR angiosarcoma cells were grown in vivo and gene expression effects of treatment were assessed with whole exome RNA sequencing. MAPK signaling was found active in over half of clinical angiosarcoma samples. Inhibition of MAPK signaling with the MEK inhibitor trametinib decreased the viability of angiosarcoma cells. Combined inhibition of the VEGF and MAPK pathways with cediranib and trametinib had an additive effect in in vitro models, and a combinatorial effect in an in vivo model. Combined treatment led to smaller tumors than treatment with either agent alone. RNA-seq demonstrated distinct expression signatures between the trametinib treated tumors and those treated with both trametinib and cediranib. These results indicate a clinical study of combined VEGFR and MEK inhibition in angiosarcoma is warranted.
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http://dx.doi.org/10.1038/s41598-021-88703-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8087824PMC
April 2021

Ferroptosis as a mechanism to mediate p53 function in tumor radiosensitivity.

Oncogene 2021 May 29;40(20):3533-3547. Epub 2021 Apr 29.

Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.

Ferroptosis, a form of regulated cell death triggered by lipid peroxidation, was recently identified as an important mechanism in radiotherapy (RT)-mediated tumor suppression and radioresistance, although the exact genetic contexts in which to target ferroptosis in RT remains to be defined. p53 is the most commonly mutated gene in human cancers and a major effector to RT. Here, we identify ferroptosis as a critical mechanism to mediate p53 function in tumor radiosensitivity. Mechanistically, RT-mediated p53 activation antagonizes RT-induced SLC7A11 expression and represses glutathione synthesis, thereby promoting RT-induced lipid peroxidation and ferroptosis. p53 deficiency promotes radioresistance in cancer cells or tumors at least partly through SLC7A11-mediated ferroptosis inhibition. Ferroptosis inducers (FINs) that inhibit SLC7A11 exert significant radiosensitizing effects in tumor organoids and patient-derived xenografts with p53 mutation or deficiency. Finally, we show that RT-induced ferroptosis correlates with p53 activation and better clinical outcomes to RT in cancer patients. Together, our study uncovers a previously unappreciated role of ferroptosis in p53-mediated radiosensitization and suggest using FINs in combination with RT to treat p53-mutant cancers.
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http://dx.doi.org/10.1038/s41388-021-01790-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8141034PMC
May 2021

Expression of B7-H4 and IDO1 is associated with drug resistance and poor prognosis in high-grade serous ovarian carcinomas.

Hum Pathol 2021 Jul 19;113:20-27. Epub 2021 Apr 19.

Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. Electronic address:

High-grade serous ovarian carcinoma (HGSC) is the most lethal gynecologic malignancy. While immune checkpoint inhibitors against PD-L1 and CTLA-4 have shown significant effects in multiple tumor types, the response rate to single-agent immune checkpoint inhibitors is low in HGSC. Alternative biomarkers and targets must be identified to guide patient selection and new therapeutic strategies in HGSC. Here, we aim to investigate the clinical significance of novel immune modulators, including B7-H4, IDO1, Tim3, IL6, and IL-8, in patients with HGSC. A total of 48 patients with HGSCs, comprising 24 cases that were sensitive and 24 that were resistant to standard paclitaxel and carboplatin chemotherapy, were selected for our initial analysis. A NanoString assay including 33 immune-related genes was used to compare the expression of different immune regulatory molecules in the sensitive and resistant groups. Differentially expressed proteins were verified using multiplex immunohistochemical staining on tissue arrays of 202 patients with HGSCs who underwent primary surgery at MDACC. We analyzed the expression levels of immune checkpoints and compared expression profiles with clinicopathologic features including response, progression-free survival, and overall survival. HGSC tumors resistant to therapy expressed higher levels of B7-H4 (69.3%), IDO1 (71.8%), Tim3 (89.1%), and inflammatory factors IL-6 and IL-8, and expressed higher Tim3 in stromal components. High expression of B7-H4 and IDO1 was associated with significantly lower overall survival and progression-free survival. B7-H4 and IDO1 were co-expressed in 49.1% of studied cases. A panel of immunomodulatory proteins including B7-H4, IDO1, Tim3, IL-6, and IL-8 are expressed at high levels in HGSCs. These modulators represent novel targets to enhance immunotherapy in patients with HGSCs.
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http://dx.doi.org/10.1016/j.humpath.2021.04.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8219231PMC
July 2021

Timing of surgery in patients with partial response or stable disease after neoadjuvant chemotherapy for advanced ovarian cancer.

Gynecol Oncol 2021 Jun 16;161(3):660-667. Epub 2021 Apr 16.

Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. Electronic address:

Objective: The ideal number of neoadjuvant chemotherapy (NACT) cycles prior to interval tumor-reductive surgery (iTRS) for advanced ovarian cancer is poorly defined. We sought to assess survival stratified by number of NACT cycles and residual disease following iTRS in patients with advanced ovarian cancer with partial response (PR) or stable disease (SD) following 3-4 cycles of NACT.

Methods: We retrospectively identified patients with advanced high-grade ovarian cancer (diagnosed 2/1/2013 to 2/1/2018) who received at least 3 cycles of NACT and iTRS and had a PR or SD. The population was divided into four groups based on the number of NACT cycles prior to iTRS and residual disease status after (CGR [complete gross residual] or incomplete resection [any amount of residual disease]): 1) 3-4 NACT cycles/CGR, 2) 3-4 NACT cycles/incomplete resection, 3) > 4 cycles/CGR, and 4) >4 cycles/incomplete resection. Overall survival (OS) and progression-free survival (PFS) were estimated using a Kaplan-Meier product-limit estimator and modeled using univariable and multivariable Cox proportional hazards analysis.

Results: The cohort consisted of 265 patients with advanced high-grade ovarian cancer with a median age at diagnosis of 65 years. Most were White (87%), had serous histology (89%), and stage IV disease (57%), with an overall CGR rate of 81%. In a multivariable analysis receipt of >4 NACT cycles was not associated with worse PFS or OS (adjusted hazard ratio [aHR] 1.02, 95% CI 0.74-1.42; aHR 1.12, 95% CI, 0.73-1.72 respectively) than was receipt of 3-4 cycles. Any amount of residual disease was associated with worse PFS and OS regardless of the number of NACT cycles (aHR 1.56, 95% CI 1.09-2.22; aHR 2.38, 95% CI 1.52-3.72 respectively).

Conclusions: Residual disease was associated with worse survival outcomes regardless of the number of NACT cycles in patients with PR or SD after NACT for advanced high-grade ovarian cancer. These data suggest that the ability to achieve CGR should take precedence in decision-making regarding the timing of surgery.
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http://dx.doi.org/10.1016/j.ygyno.2021.04.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8165031PMC
June 2021
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