Advanced-stage Cancer Research Articles

Abstract 3083: Unveiling the role of chemotherapy-resistant, slow-cycling cancer cells in driving cancer cachexia

Abstract Cancer cachexia, a systemic disease marked by substantial, involuntary weight loss, predominantly affecting muscle and adipose tissue, manifests in patients with advanced-stage cancer. The emergence of cancer cachexia poses significant challenges to cancer treatment, diminishing the efficacy of anticancer medications, and the resultant muscle loss adversely impacts the daily lives of patients, diminishing the overall quality of life. Notably, cancer cachexia is implicated in 30-40% of cancer-related deaths, underscoring the pivotal need to comprehend its underlying principles and propose apt interventions to enhance both survival rates and the well-being of cancer patients. Based on our previous findings, cancer cells exhibiting a slow cell cycle, resistant to widely employed clinical chemotherapy agents, exhibit the formation of proinflammatory tumor microenvironment. The escalation of systemic inflammatory cytokines has long been suggested as a potential mechanism contributing to cancer cachexia. Building upon these insights, we hypothesized that slow-cycling cancer cells (SCCs) featuring resistance to chemotherapy are pivotal contributors to cancer cachexia. We investigated the impact of drug-resistant SCCs on the loss of differentiated myotubes and lipid droplets in vitro and muscle and fat loss in in vivo conditions. Interestingly, these cells induced more severe muscle and fat losses. Upon scrutinizing this cell population, we found the overexpression of a particular membrane protein, Protein A. The increase of this Protein A enhanced the release of exosomes from the cell through a novel mechanism distinct from its classical functions, consequently amplifying the release of inflammatory substances originating from cancer cells. In summary, our study elucidates that chemotherapy-resistant cancer cells, characterized by a slow cell cycle, intensify the secretion of inflammatory substances in a manner contingent upon the overexpression of a membrane protein A, which leads to the depletion of muscle and fat located in the distal peripheral regions. Citation Format: Jaebeom Cho, Ho-Young Lee. Unveiling the role of chemotherapy-resistant, slow-cycling cancer cells in driving cancer cachexia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3083.

Abstract 5690: Urinary microRNA expression in pancreatic cancer with cachexia

Abstract Background: Cancer cachexia (CC) is a multifactorial syndrome characterized by appetite loss, weight loss and skeletal muscle wasting. It increases functional impairment, treatment-related toxicity, and a lower quality of life. Importantly, CC is one of the leading causes of cancer-related deaths, and its occurrence is particularly prevalent in advanced stages of pancreatic cancer (PC). The syndrome is thought to be associated with systemic inflammation and increased energy expenditure, yet the specific mechanisms remain to be fully understood. Although timely detection and intervention might be crucial in preventing CC’s progression, early diagnosis of this syndrome remains challenging due to the absence of suitable biomarkers. Here, we analyzed urinary microRNAs (miRNAs) as a potential noninvasive biomarkers for detecting CC in patients (pts) with PC. Methods: Clinical information including presence or absence of CC and urine samples were collected from pts with PC treated at National Cancer Center Hospital, Tokyo, Japan from March to October 2022. The diagnosis of CC was made according to the following definitions by Fearon. K et al. (1) weight loss of ≥5% within 6 months; (2) weight loss of ≥2% in pts with a BMI of <20 kg/m2; or (3) weight loss of ≥2% in pts with sarcopenia. In this study, pts who met the definition of CC within 6 months of enrollment were considered to have CC.Urinary miRNA profiles from pts with PC were sequenced by NGS and analyzed using DESeq2 to identify differentially expressed miRNAs (DEMs) between pts with CC and those without. DEMs were further explored for associated pathways and target genes using miRPathDB v.2.0. Results: Of the 64 subjects, 52 pts were included in the analysis after excluding three pts with low urine sample read coverage and nine pts with no information on CC status. Among those, 38 pts were classified as having CC. Patients’ background was as follows (CC/no CC); median age 70 [range: 44-80]/67 [57-74], male and female 19/7 pts, respectively, cStage {I (6/0), II (1/0), III (17/4), IV (14/10)} pts, median BMI (male 22.1 [17.7-27.2]/21.7 [18.2-28.2], female 21.7 [14.6-25.2]/21.9 [16.6-27.4]) kg/m2. Among 307 miRNAs detected in the urine of pts with PC, 49 miRNAs had previously been reported in CC research. The miR-141-5p was differentially expressed between pts with CC and those without CC (Wald test pBH = 0.079). It was down-regulated in pts with CC (Mann-Whitney U test p = 6.4e-4) and most significantly associated with the FoxO signaling pathway (ORA pBH = 1.84e-4), followed by the mTOR signaling pathway (ORA pBH = 0.008). Conclusions: Our study indicates that miR-141-5p holds potential as a noninvasive biomarker for the detection of CC in pts with PC. Although miR-141-5p has not been previously reported in CC, its significant association with the FoxO signaling pathway, which is one of the major pathways regulating skeletal muscle atrophy, underscores the relevance of miR-141-5p in the context of CC. Citation Format: Mao Okada, Shunsuke Kondo, Yukiko Igawa, Tatsuya Yoshida, Milos Havelka, Mika Mizunuma, Yuki Ichikawa, Noboru Yamamoto. Urinary microRNA expression in pancreatic cancer with cachexia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5690.

Abstract 5577: TRPM8 mediated Ca2+ signaling as a therapeutic target in prostate cancer

Abstract Prostate cancer (PC) is a prevalent and deadly malignancy, necessitating the development of innovative therapeutic strategies. Transient receptor potential melastatin 8 (TRPM8), an ion channel highly expressed in prostate epithelium, has emerged as a potential target. Our preliminary studies demonstrate that TRPM8 plays a crucial role in PC progression. We observed an initial increase in TRPM8 mRNA expression during early-stage PC, followed by a decline in advanced and androgen-independent prostate cancer (AIPC) stages. Additionally, TRPM8 knockout mice exhibited elevated serum testosterone levels, heightened androgen receptor (AR) activity, and increased cell cycle, invasion, and adhesion-related effects. In xenograft models, TRPM8 demonstrated potent antitumor properties in both AR+ and AR- contexts. Our research suggests that TRPM8 activation on the plasma membrane promotes calcium influx and induces apoptosis in PC cells. Conversely, TRPM8 internalization correlates with PC pathogenesis. By exploring the effects of TRPM8 on PTEN-mediated cellular signaling, we aim to uncover novel insights into the molecular mechanisms underlying TRPM8's role in PC. This abstract underscores the potential of targeting TRPM8-mediated Ca2+ signaling as a promising therapeutic approach to combat PC progression, offering hope for improved patient outcomes. Citation Format: Swapna Asuthkar, Kiran Velpula, Vander Don Griend. TRPM8 mediated Ca2+ signaling as a therapeutic target in prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5577.

Abstract 104: Profiling peripheral blood to predict response to targeted androgen receptor axis therapy in mice

Abstract Background: Targeting the androgen receptor (AR) signaling axis (ARAT) continues to be the mainstay treatment for advanced-stage prostate cancer. Using second-generation antiandrogens like abiraterone acetate (Abi) and apalutamide (Apa) has contributed to the survival of prostate cancer patients. However, resistance to these therapies remains a problem and most of these patients progress to castration-resistant prostate cancer (CRPC). Myeloid-derived suppressor cells (MDSCs) have been shown to drive CRPC. We previously showed that unfavorable responses to androgen deprivation therapy (ADT) or ADT plus Apa were associated with polymorphonuclear MDSCs (PMN-MDSCs) cells enriched in prostate tumors from conditional Pten/Trp53-double knockout (DKO) mice. Here, we explore the association between pre-treatment immune cell subsets blood and antitumor to ARAT therapy DKO mice. Methods: Twenty-eight-week-old DKO mice were surgically castrated and after four weeks were randomized to treatments with vehicle, Apa or Abi for an additional four weeks (n=20). Individual treatment responses were assessed and classified according to tumor burden as follows: high tumor burden (HTB), ≥20% of median; moderate tumor burden (MTB), -20% to 20% of median; or low tumor burden (LTB), ≤-20% of median. Peripheral blood was collected both before and after treatment and analyzed by multi-color flow cytometry panels for lymphoid and myeloid subsets. Blood samples from healthy wildtype and untreated DKO mice with castration-naïve prostate tumors were collected as reference samples. Subsets of PMN-MDSCs and monocytic-MDCSs (m-MDSCs) were represented as % of total abundance and 5 of parental population. revealed a signature that was correlated with treatment responses. Profiles were constructed and the data was used to train supervised learning models to predict treatment responses. Shapely additive explanations (ShAP) were used to determine feature importance. The model was tested and validated on an independent cohort of 20 DKO mice treated with ADT and ADT plus Abi. Results: Moderate prediction from baseline blood could be identified for tumor burden following ARAT using a Naïve Bayes classifier. Model evaluation, using an independent cohort, yielded favorable performance with area under the curve (AUC) mean, 0.707; HTB, 0.627; MTB, 0.750; and LTB, 0.745. The most important features for prediction were identified. Conclusion: Our study revealed that MDSC subsets present in blood were associated with treatment responses to ARAT. Citation Format: Marco A. De Velasco, Yurie Kura, Kazuko Sakai, Yoshitaka Saito, Takafumi Minami, Kazuhiro Yoshimura, Kazutoshi Fujita, Kazuto Nishio, Hirotsugu Uemura. Profiling peripheral blood to predict response to targeted androgen receptor axis therapy in mice [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 104.

Optimisation Studies of Mesoporous Silica Nanoparticle as a Drug Carrier for Gemcitabine: Enhancing Therapeutic Effectiveness in Pancreatic Cancer

Pancreatic cancer, often referred to as “the silent killer”, presents with minimal or no symptoms in its early stages, leading to late detection when surgical resection is no longer the optimal treatment option. Gemcitabine (GEM), one of the leading chemotherapeutic drug for advanced stages of cancer, is a crucial treatment for pancreatic cancer. However, the low 5-year survival rate of pancreatic cancer patients highlight the limited effectiveness of current treatments. In recent years, mesoporous silica nanoparticles (MSNP) have garnered significant attention in both scholarly and pharmaceutical fields due to their unique combination of properties including stable porous structure and high loading capacities. This research aims to investigate the potential of MSNP as a carrier for anticancer drugs, specifically GEM. MSNP was successfully synthesized in the laboratory using sol-gel method with tetraethyl orthosilicate (TEOS) as silica source and cetyltrimethylammonium bromide (CTAB) as surfactant template. Comprehensive morphological and physical characterizations of the MSNP product were performed through transmission electron microscopy (TEM), field emission scanning electron microscopy (FESEM), energy dispersive X-ray (EDX) spectroscopy, element mapping, X-ray diffractometry (XRD), and accelerated surface area porosimetry (ASAP). The results demonstrate that MSNP exhibits desirable properties for drug loading, including a stable mesoporous structure with pore size of ~ 4.94 nm, a high surface area of about 278.32 m²/g, and average particle diameter of approximately 85 nm. The effects of incubation time and initial GEM concentrations were studied to determine the optimal drug loading parameters for the MSNP vehicle. The successful loading of up to 24 µg of GEM in 1 mg of MSNP achieved in an optimized incubation time of 2 hour, validates the tremendous potential of MSNP as a potential anticancer drug carrier in pancreatic cancer treatment. These findings provide a valuable reference for future research and investigations in this promising field.

Abstract 1298: Assessing the impact of Medicaid expansion on colorectal cancer preventative services utilization

Abstract Introduction: Colorectal cancer (CRC) is the second leading cause of cancer mortality. CRC screening rates have steadily risen and incidence rates around the nation have declined. To date, forty-one states have expanded Medicaid across the United States, with 9 states remaining that have not expanded. Although, access through insurance has increased, colorectal disparities in screening and mortality persist. Other studies have shown that screening guideline concordance can be inconsistent based on insurance type. Data suggests Medicaid enrollees are more likely to present advanced-stage cancers than those privately enrolled. The screening differences throughout the United States emphasize how complex colorectal cancer disparities are and how insurance may play a role. Aims: Our study aims to investigate the impact of Medicaid expansion on timely CRC screenings, specifically examining whether these effects differ by African Americans, Hispanics, and White Americans. Methods: Data was utilized from the Behavioral Risk Factor Surveillance System (BRFSS) to analyze timely CRC screening data of adults below 138% of the federal poverty level (FPL) of states with different Medicaid expansion statuses. Most recently available data was used in our analysis spanning the years 2014-2022 in all 50 states. States were stratified by dummy variables for Medicaid expansion and non-expansion status. Timely CRC screenings were determined by eligible respondent responses. Difference-in-difference analyses were used to study the effect of Medicaid expansion on timely CRC screenings in states with different Medicaid expansion statuses. Results: Our sample included 60.52% White Americans, 12.22% African Americans, and 16.41% Hispanics in both Medicaid expanded and non-expanded states. Sex and race had significant associations to Medicaid expansion status and timely CRC screenings, particularly when analyzing race for Hispanics and White Americans. Between 2014 and 2022, timely CRC screening for low-income adults in Medicaid expansion states was at 33.15% compared to 23.17% from non-expansion status states. Notably, adults aged 45-64 demonstrated the highest differences in timely CRC screenings for Medicaid-expanded states (12.26% and 18.98%) compared to non-expanded states (9.27% and 13.96%, respectively). Citation Format: Paulette Omeaku. Assessing the impact of Medicaid expansion on colorectal cancer preventative services utilization [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1298.

Abstract 6124: A comprehensive pan-cancer study nominating NF-κB-mediated TNFA signaling-induced hypoxia as a risk factor in Hispanic cancer progression

Abstract The Hispanic (HA) population is the second largest racial/ethnic group in the United States after non-Hispanic White (NHW). Though the HA population usually has a lower reported incidence of cancers compared to NHW, there are racial disparities exist in the mortality rate of some of the cancers. Factors related to the Social Determinants of Health (SDOH), such as higher poverty rates, less education, and reduced access to health care, are known to increase the risk of diagnosing advanced-stage cancer in HA compared to the NHW population. The contribution of such SDOH in the HA cancer population has been studied in the past years. However, the contribution of biological and genetic mechanisms to HA cancer disparity has not been well understood. Thus, in this study, we performed a comprehensive analysis of different databanks to understand the common genetic and biological factors that contribute to the pan-cancer disparity in the HA population. To identify HA and NHW populations, we used self-reported racial/ethnic information. Analysis of the “All of Us” database suggested a high prevalence of infection-related cancers such as Liver, Stomach, and Cervix Uteri in the HA population compared to the NHW population. SEER database also showed an increased percentage of diagnoses with infection-related cancers and poor survival of the HA population with these cancers compared to the NHW. We then analyzed the TCGA transcriptome data from primary tumors from HA and NHW patients. We only selected cancers with data from at least ten patients in each group. TCGA data confirmed that the tumors from HA cancer patients primarily express high inflammatory and immune-responsive signatures. Specifically, we found a high enrichment of NF-κB induced TNFA signaling in HA tumors. We also observed a significant correlation between TNFA and Hypoxia signature in many HA cancers. Since hypoxia is known to be associated with resistance to radiation and chemotherapy, targeting the increased hypoxia signature in HA tumors may be critical for sensitizing HA patients to cancer therapy. Overall, our pan-cancer analyses suggest an increased prevalence of many infection-related cancers in the HA population. HA tumors are enriched with TNFA, NF-κB, and hypoxic signatures. Specific targeting of these signatures may be critical in managing the HA patients who currently suffer from racial disparity in cancer incidence and survival. Citation Format: Tagari Samanta, Jun Hyoung Park, Benny Abraham Kaipparettu. A comprehensive pan-cancer study nominating NF-κB-mediated TNFA signaling-induced hypoxia as a risk factor in Hispanic cancer progression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6124.

Abstract 7358: Role of noncoding genome architecture in esophageal cancer

Abstract Esophageal Cancer is a deadly disease with a tendency to be diagnosed at the later stages. Considered a rare disease, accounting for 1.1% of all cancers, EC comprises 2.6% of all cancer deaths. The survival rate for all stages is 21.7%. However, the survival rate decreases to 5.6 % for advanced-stage cancers. EC is more common in men and associated with older age and heavy alcohol and tobacco use. In the last 25 years, the death rate of EC has been decreasing slightly from 4.3 to 3.7. The death rates for lung, prostate, and colon cancers have decreased by half in the same time frame. Therefore, novel therapies and biomarkers are urgently needed to accelerate survival and reduce the death rates by at least half for patients with EC.We previously completed exome sequencing in a small sample size and observed that the mutations in the noncoding regions of the EC genome are highly affected. In this study, we perform exome sequencing in 110 paired esophageal tumors and normal tissues using an Agilent SSELXT HS Exon V8+UTR library enrichment kit. Twelve paired EC and normal tissues are sequenced using the PacBio Hifi system.In WES, we detected almost half of the noncoding region mutations in the 3UTR and 2kb downstream regions of the genome, significantly affecting 51 oncogenic or tumor suppressor genes. In addition, the involved genes are over-represented in critical signaling pathways and transcriptional regulation of pluripotent stem cells. The number of changes in the 5UTR and 2kb upstream are similar to the number of variations in the intronic regions. Apoptosis, stress response, and DNA double-strand break repair pathways are affected by 5UTR mutations. Mutations in the intronic regions frequently occurred in pro-tumorigenic immune regulation genes, such as IL-33 and IL-6, and oncogene-induced senescence.The combined effect of these genetic and coding region mutations on oncogenes, significant signaling pathways, cancer cell stemness, DNA damage repair pathways, and immune system regulation may significantly impact poor prognosis in EC patients. Further studies will verify the effectiveness of targeting these genes for developing candidate therapeutics. Citation Format: Hayriye Verda Erkizan, Robert Wadleigh. Role of noncoding genome architecture in esophageal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7358.

Single cell deciphering of progression trajectories of the tumor ecosystem in head and neck cancer

Head and neck squamous cell carcinoma is the sixth most common cancer worldwide and has high heterogeneity and unsatisfactory outcomes. To better characterize the tumor progression trajectory, we perform single-cell RNA sequencing of normal tissue, precancerous tissue, early-stage, advanced-stage cancer tissue, lymph node, and recurrent tumors tissue samples. We identify the transcriptional development trajectory of malignant epithelial cells and a tumorigenic epithelial subcluster regulated by TFDP1. Furthermore, we find that the infiltration of POSTN+ fibroblasts and SPP1+ macrophages gradually increases with tumor progression; their interaction or interaction with malignant cells also gradually increase to shape the desmoplastic microenvironment and reprogram malignant cells to promote tumor progression. Additionally, we demonstrate that during lymph node metastasis, exhausted CD8+ T cells with high CXCL13 expression strongly interact with tumor cells to acquire more aggressive phenotypes of extranodal expansion. Finally, we delineate the distinct features of malignant epithelial cells in primary and recurrent tumors, providing a theoretical foundation for the precise selection of targeted therapy for tumors at different stages. In summary, the current study offers a comprehensive landscape and deep insight into epithelial and microenvironmental reprogramming throughout initiation, progression, lymph node metastasis and recurrence of head and neck squamous cell carcinoma.

Abstract 6657: Oncolytic Vaccinia Virus Carrying OPCML Tumor Suppressor is active in Epithelial Ovarian Cancer

Abstract Objective: Epithelial Ovarian cancer (EOC) has the highest mortality rate among gynecologic malignancies, necessitating novel therapeutic approaches. Viral oncolytic immunotherapy with recombinant oncolytic vaccinia virus (OVV) offers promise for advanced-stage cancer treatment. OPCML is a GPI-anchored 3 Ig-domain tumor suppressor inactivated by somatic methylation in 87% of EOC. OVV with OPCML (OVV-OPCML) gene insertion may have potential as a therapeutic agent. This study explores the oncolytic, signaling-inhibitory, anti-angiogenic and synergistic immunotherapeutic properties of OVV-OPCML in EOC treatment, evaluating its therapeutic potential. Methods: To create OVV-OPCML, the virulent vaccinia virus Copenhagen strain F3L site was modified with OPCML cDNA, confirmed by qPCR and western blot. Oncolytic potential was assessed through in vitro and in vivo EOC cell infection with OVV-OPCML. Real-time cell analysis (RTCA) assessed cell proliferation. Xenograft tumor models in nude mice were used to evaluate in vivo oncolytic activity, while OVV-OPCML combined with anti-PD-1 treatment was tested using a syngeneic orthotopic EOC mouse model (ID8) in C57BL/6 immunocompetent mice. Serum IFN-γ and TNF-α were quantified via ELISA. Receptor Tyrosine Kinases, angiogenesis and phosphorylation together with immune markers were examined by western blotting and by multiplex immunohistochemistry (mIHC) analysis of tumor sections. Results: OVV-OPCML selectively infected OC cells, leading to viral replication and tumor cell death, while sparing normal ovarian cells in-vitro. OPCML protein expression increased post-infection. OVV-OPCML reduced ERBB2, EGFR, and FGFR1 expression in SKVO3 OV cells. Intratumoral or intraperitoneal (IP) OVV-OPCML administration in human ovarian cancer nude mouse models reduced tumor growth and improved survival. IP in-vivo OVV-OPCML in combination with anti-PD-1 treatment in vivo, in the IP ID8 syngeneic model demonstrated synergy with survival improvement. H&E staining showed tumor cell damage without significant harm to normal tissues. Protein expression of ERBB2, EGFR, FGFR1, and their phosphorylated forms decreased. CD31, VEGFR2, p-VEGFR2 (Tyr1175), and p-VEGFR2 (Tyr1214) downregulation suggested tumor angiogenesis disruption. OVV-OPCML treatment elevated serum TNF-α and INF-γ levels and increased CD8+ T cells and PD-L1 expression in OVV-OPCML treated syngeneic tumors. Conclusions: OPCML gene enhances OVV selectivity against OC cells through direct oncolysis and OPCML protein production, inhibiting specific RTKs, suppressing angiogenesis, and activating antitumor immune responses synergistically with anti-PD-1. OVV-OPCML therapy shows promise as a targeted strategy for ovarian cancer treatment. Citation Format: Yong Tang, Yingzhao Liu, Mingjing Deng, Fei Huang, Jiahu Wang, Paul Blake, Hani Gabra, Qi Wang. Oncolytic Vaccinia Virus Carrying OPCML Tumor Suppressor is active in Epithelial Ovarian Cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6657.

Abstract 5691: Identification of miRNA related to triple-negative breast cancer in African and European American women with obesity

Abstract Triple-negative breast cancer (TNBC) represents 10-20% of all invasive breast cancers and is characterized by a lack of expression of estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2. TNBC typically manifests as high-grade tumors often diagnosed at advanced stages, and affects younger patients, especially African American (AA) women. Dysregulation of miRNA expression levels contributes to TNBC pathogenesis and prognosis. Dysregulated miRNAs in advanced-stage cancers alter tumor progression, migration, and metastasis. Obesity is associated with miRNA dysregulation in adipose tissue, which is a driver of BC development and growth. This study aimed at identifying differentially expressed (DE) miRNA in TNBC patients of European American (EA) and AA women with obesity, compared to adjacent non-tumor tissues. miRNAseq data from 48 tissue samples (TNBC tumor and adjacent non-tumor) were analyzed for differential expression. Samples were from 12 EA and 12 AA patients, with 6 patients in each ethnic group having obesity and 6 normal weight, based on BMI estimates. Stringent comparisons, with and without obesity, were conducted to identify TNBC and obesity-associated miRNAs within each ethnic group. Prediction of miRNA-target genes was performed in miRWalk and Key Pathway Advisor (KPA) was employed for pathway enrichment analysis. Differential expression analysis between obese and normal-weight patients in each ethnic group revealed 79 DE miRNAs in EA and 40 in AA. We identified 55 miRNAs associated exclusively with tumors in obese patients within the EA group and 33 miRNAs within the AA group. Target gene analysis showed that in EA, 9 out of the 55 miRNAs interacted with 68 mRNAs, with miR-204-5p and miR-181b-5p accounting for 75% of interactions. In AA, 20 out of the 33 miRNAs interacted with 284 mRNAs with miR-20a-5p, -195-5p, -34a-5p, and -130a-3p with 65% of the interactions. KPA identified 84 and 330 pathways for EA and AA, respectively, with 43 common pathways,15 of them related to cancer processes sharing the gene targets GSKIP, TLBR1, TCF4, and TCF. Our study outlined unique miRNA profiles in TNBC among AA and EA women with obesity. Although common mRNAs were identified between ethnic groups, leading to the identification of common pathways on KPA, more than 50% of the identified pathways are related to unique biological processes associated with TNBC and obesity for each ethnic group. These findings underscore the importance of considering ethnic-specific miRNA signatures for understanding TNBC in the context of obesity, offering insights for targeted therapeutic strategies. Citation Format: Fokhrul Hossain, Martha Isabel González-Ramírez, Jone Garai, Xiao-Cheng Wu, Chindo Hicks, Luis Del Valle, Augusto Ochoa, Denise Danos, Lucio Miele, Jovanny Zabaleta. Identification of miRNA related to triple-negative breast cancer in African and European American women with obesity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5691.

A Comprehensive Study on Folate-Targeted Mesoporous Silica Nanoparticles Loaded with 5-Fluorouracil for the Enhanced Treatment of Gynecological Cancers.

Gynecological cancers are a significant public health concern, accounting for 40% of all cancer incidence and 30% of deaths in women. 5-Fluorouracil (5-FU) can be used with chemotherapy to improve treatment in advanced-stage gynecological cancer. Mesoporous silica nanoparticles (MSNs) can improve drug effectiveness and reduce toxicity. Folic acid can target folate receptors in epithelial malignancies like ovarian and cervical cancer. The mixture of MSN-NH2 was synthesized by dissolving N-lauroylsarcosine sodium in a water-ethanol mixture, adding APTES and TEOS, and heating at 80 °C for 18 h, before being fully characterized. The drug is loaded into a 5-FU solution and functionalized with folate. The drug release mechanism, as well as ex vivo intestinal permeation from MSN-NH2 formulations, was tested. The cell viability study of the nanoparticles was evaluated in various cancer cell lines, and the cellular uptake was measured indirectly using HPLC. The study analyzed the amine content, propylamine loading, and drug loading capacity of MSN-NH2 nanoparticles. It found that the loading of propylamine was around 0.733 mmol/g, and the surface density was 0.81 molecules/nm. The study also showed that the surface decoration of MSN-NH2 with folic acid was successfully achieved. The release rate of 5-FU from MSN-NH2 was slow and controlled, with a slower rate at pH 5.5. The study found that the amin surface functionalization of MSN-NH2 nanoparticles can reduce potential toxicity in ovarian and cervical cancer cells. Based on the results, the encapsulation of 5-FU and functionalization of MSN-NH2 with folic acid can serve as potential carriers for 5-FU in treating gynecological cancer.

Liver cancer treatment with mitochondrial homeostasis

Systemic treatment, including molecular targeted therapy, immunotherapy, and chemotherapy, is an important means of achieving long-term survival in patients with intermediate-and advanced-stage liver cancer. However, some patients are insensitive to treatment and even develop drug resistance. Mitochondria are the center of cellular energy metabolism and, at the same time, are the priority targets for systemic therapy. Mitochondrial homeostasis plays an important role in the treatment of liver cancer. The relationship between the two advances is elucidated so as to provide better ideas for the clinical treatment of liver cancer.

Claudin 18.2 as a novel therapeutic target.

Claudin 18.2, a tight-junction molecule predominantly found in the nonmalignant gastric epithelium, becomes accessible on the tumour cell surface during malignant transformation, thereby providing an appealing target for cancer therapy. Data from two phase III trials testing the anti-claudin 18.2 antibody zolbetuximab have established claudin 18.2-positive advanced-stage gastric cancers as an independent therapeutic subset that derives benefit from the addition of this agent to chemotherapy. This development has substantially increased the percentage of patients eligible for targeted therapy. Furthermore, newer treatments, such as high-affinity monoclonal antibodies, bispecific antibodies, chimeric antigen receptor T cells and antibody-drug conjugates capable of bystander killing effects, have shown considerable promise in patients with claudin 18.2-expressing gastric cancers. This new development has resulted from drug developers moving beyond traditional targets, such as driver gene alterations or growth factors. In this Review, we highlight the biological rationale and explore the clinical activity of therapies that target claudin 18.2 in patients with advanced-stage gastric cancer and explore the potential for expansion of claudin 18.2-targeted therapies to patients with other claudin 18.2-positive solid tumours.

Synchronous versus metachronous spinal metastasis: a comparative study of survival outcomes following neurosurgical treatment

PurposePatients with spinal metastases (SM) from solid neoplasms typically exhibit progression to an advanced cancer stage. Such metastases can either develop concurrently with an existing cancer diagnosis (termed metachronous SM) or emerge as the initial indication of an undiagnosed malignancy (referred to as synchronous SM). The present study investigates the prognostic implications of synchronous compared to metachronous SM following surgical resection.MethodsFrom 2015 to 2020, a total of 211 individuals underwent surgical intervention for SM at our neuro-oncology facility. We conducted a survival analysis starting from the date of the neurosurgical procedure, comparing those diagnosed with synchronous SM against those with metachronous SM.ResultsThe predominant primary tumor types included lung cancer (23%), prostate cancer (21%), and breast cancer (11.3%). Of the participants, 97 (46%) had synchronous SM, while 114 (54%) had metachronous SM. The median overall survival post-surgery for those with synchronous SM was 13.5 months (95% confidence interval (CI) 6.1–15.8) compared to 13 months (95% CI 7.7–14.2) for those with metachronous SM (p = 0.74).ConclusionsOur findings suggest that the timing of SM diagnosis (synchronous versus metachronous) does not significantly affect survival outcomes following neurosurgical treatment for SM. These results support the consideration of neurosurgical procedures regardless of the temporal pattern of SM manifestation.

Structured screening for sporadic breast cancer

The aim of secondary prevention of breast cancer is to detect the disease at the earliest curable stage and thus to reduce breast cancer-specific mortality. To this end, the nationwide population-based mammography screening program (MSP) was set up in Germany in 2005 in addition to an interdisciplinary prevention project for high-risk groups. Overview of the current state of the MSP, the upcoming age expansion, and potential further developments. Narrative review article with topic-guided literature and data search. Approximately 50% of the 70,500 new cases of breast cancer that occur each year are related to the age group of the MSP. 10years after introduction of the MSP, the incidence of advanced breast cancer stages and breast cancer-related mortality of the screening target group have steadily decreased by about one quarter, while no relevant trends were seen in the neighboring age groups at the population level. The MSP has effectively contributed to areduction of breast cancer mortality. With the expansion of the age groups to 45-75years, more women have access to structured, quality assured screening. With the use of advanced stratifications and diagnostics as well as artificial intelligence, the MSP could be further optimized.

The economic burden of cervical cancer on women in Uganda: Findings from a cross-sectional study conducted at two public cervical cancer clinics.

There is limited research on how a cervical cancer diagnosis financially impacts women and their families in Uganda. This analysis aimed to describe the economic impact of cervical cancer treatment, including how it differs by socio-economic status (SES) in Uganda. We conducted a cross-sectional study from September 19, 2022 to January 17, 2023. Women were recruited from the Uganda Cancer Institute and Jinja Regional Referral Hospital, and were eligible if they were ≥ of 18 years and being treated for cervical cancer. Participants completed a survey that included questions about their out-of-pocket costs, unpaid labor, and family's economic situation. A wealth index was constructed to determine their SES. Descriptive statistics were reported. Of the 338 participants, 183 were from the lower SES. Women from the lower SES were significantly more likely to be older, have ≤ primary school education, and have a more advanced stage of cervical cancer. Over 90% of participants in both groups reported paying out-of-pocket for cervical cancer. Only 15 participants stopped treatment because they could not afford it. Women of a lower SES were significantly more likely to report borrowing money (higher SES n = 47, 30.5%; lower SES n = 84, 46.4%; p-value = 0.004) and selling possessions (higher SES n = 47, 30.5%; lower SES n = 90, 49.7%; p-value = 0.006) to pay for care. Both SES groups reported a decrease in the amount of time that they spent caring for their children since their cervical cancer diagnosis (higher SES n = 34, 31.2%; lower SES n = 36, 29.8%). Regardless of their SES, women in Uganda incur out-of-pocket costs related to their cervical cancer treatment. However, there are inequities as women from the lower SES groups were more likely to borrow funds to afford treatment. Alternative payment models and further economic support could help alleviate the financial burden of cervical cancer care in Uganda.

A Retrospective Cross-Sectional Study on the Effect of Socio-Cultural Factors and Edication in Early Detection of Breast Cancer

Backgrounds: The aim of this study is to investigate the preferences of female patients regarding the choice of surgeon for breast examination and the factors impacting this preference. Methods: A questionnaire was administered by interviewing 746 patients who applied to the General Surgery outpatient clinic with complaints of breast disease, and the results were analyzed statistically. The questionnaire form included the patient's age, marital status, hormonal status, history of delivery, complaints, factors that may impact the choice of physician, educational status, physical examination findings, and imaging results. Results: The study group included 746 patients aged between 14 and 76 years. While 284 (38%) of our patients applied to the outpatient clinic within 7 days of their first symptoms, 462 (62%) applied more than 7 days later. Due to late admission, advanced-stage breast cancer was detected in 2.8% of the patients. The most common reason for the delay in admission was the feeling of embarrassment in females of all age groups. Conclusion: Women with breast disease apply to the physician in the late period due to feeling embarrassed, religious beliefs, spouse pressure, and having a reservation for being examined by a male doctor. Breast diseases could be detected and treated in an earlier period, by enabling patients to apply to a physician earlier, with training, especially for women.

Health-related quality of life and its determinants among cancer patients: evidence from 12,148 patients of Indian database

BackgroundCancer survivors experience a decrement in health-related quality of life (HRQoL) resulting from the disease as well as adverse effects of therapy. We evaluated the HRQoL of cancer patients, stratified by primary cancer site, stage, treatment response and associated adverse events, along with its determinants.MethodsData were collected from 12,148 patients, sampled from seven purposively chosen leading cancer hospitals in India, to elicit HRQoL using the EuroQol questionnaire comprising of 5-dimensions and 5-levels (EQ-5D-5L). Multiple linear regression was used to determine the association between HRQoL and various socio-demographic as well as clinical characteristics.ResultsMajority outpatients (78.4%) and inpatients (81.2%) had solid cancers. The disease was found to be more prevalent among outpatients (37.5%) and inpatients (40.5%) aged 45–60 years and females (49.3–58.3%). Most patients were found to be in stage III (40–40.6%) or stage IV (29.4–37.3%) at the time of recruitment. The mean EQ-5D-5 L utility score was significantly higher among outpatients [0.630 (95% CI: 0.623, 0.637)] as compared to inpatients [0.553 (95% CI: 0.539, 0.567)]. The HRQoL decreased with advancing cancer stage among both inpatients and outpatients, respectively [stage IV: (0.516 & 0.557); stage III (0.609 & 0.689); stage II (0.677 & 0.713); stage I (0.638 & 0.748), p value < 0.001]. The outpatients on hormone therapy (B = 0.076) showed significantly better HRQoL in comparison to patients on chemotherapy. However, palliative care (B=-0.137) and surgery (B=-0.110) were found to be associated with significantly with poorer HRQoL paralleled to chemotherapy. The utility scores among outpatients ranged from 0.305 (bone cancer) to 0.782 (Leukemia). Among hospitalized cases, the utility score was lowest for multiple myeloma (0.255) and highest for testicular cancer (0.771).ConclusionOlder age, lower educational status, chemotherapy, palliative care and surgery, advanced cancer stage and progressive disease were associated with poor HRQoL. Our study findings will be useful in optimising patient care, formulating individualized treatment plan, improving compliance and follow-up.

Arterial Thromboembolism in Japanese Patients With Cancer: Incidence, Predictors, and Survival Impact

BackgroundThromboembolism is a significant complication for patients with cancer, leading to treatment interruptions and poor outcomes. ObjectivesThe aim of this study was to investigate the incidence of arterial thromboembolism (ATE) within cancer populations, identify the predictors of ATE, and determine its survival impact. MethodsA retrospective multicenter study was performed using data from the Osaka Cancer Registry linked with administrative data from 2010 to 2015. Patients were monitored for 5 years after cancer diagnosis, and ATE incidence was calculated with death as a competing risk. Fine and Gray competing risk regression models and Cox proportional hazards models were used to evaluate the predictors of ATE and the survival impact. Restricted mean survival time (RMST) was used to assess whether antithrombotic therapy after ATE contributed to improved survival. ResultsThe cohort comprised 97,448 patients with cancer (42.3% women, median age 70 years). ATE incidence displayed an annual increase, peaking 1 year after cancer diagnosis (1-, 2-, 3-, 4-, and 5-year cumulative incidences were 1.29%, 1.77%, 2.05%, 2.22%, and 2.32%, respectively). Male sex, advanced age, advanced cancer stage, and hematologic malignancies correlated with a high risk for ATE. Patients with ATE had a 2-fold increased risk for mortality compared with those without ATE. The 90-day and 1-year RMST differences for those on antithrombotic therapy were 13.3 days (95% CI: 10.4-16.2 days; P < 0.001) and 57.8 days (95% CI: 43.1-72.5 days; P < 0.001), favoring the antithrombotic therapy group. The RMST differences varied by cancer stage. ConclusionsThe risk for ATE varies according to sex, age, and cancer progression and type. Antithrombotic therapy after ATE is associated with improved survival among patients with cancer.