Reduction Of Tumor Mass Research Articles

Gadolinium-Based Nanoparticles Sensitize Ovarian Peritoneal Carcinomatosis to Targeted Radionuclide Therapy.

Ovarian cancer (OC) is the most lethal gynecologic malignancy (5-y overall survival rate, 46%). OC is generally detected when it has already spread to the peritoneal cavity (peritoneal carcinomatosis). This study investigated whether gadolinium-based nanoparticles (Gd-NPs) increase the efficacy of targeted radionuclide therapy using [177Lu]Lu-DOTA-trastuzumab (an antibody against human epidermal growth factor receptor 2). Gd-NPs have radiosensitizing effects in conventional external-beam radiotherapy and have been tested in clinical phase II trials. Methods: First, the optimal activity of [177Lu]Lu-DOTA-trastuzumab (10, 5, or 2.5 MBq) combined or not with 10 mg of Gd-NPs (single injection) was investigated in athymic mice bearing intraperitoneal OC cell (human epidermal growth factor receptor 2-positive) tumor xenografts. Next, the therapeutic efficacy and toxicity of 5 MBq of [177Lu]Lu-DOTA-trastuzumab with Gd-NPs (3 administration regimens) were evaluated. NaCl, trastuzumab plus Gd-NPs, and [177Lu]Lu-DOTA-trastuzumab alone were used as controls. Biodistribution and dosimetry were determined, and Monte Carlo simulation of energy deposits was performed. Lastly, Gd-NPs' subcellular localization and uptake, and the cytotoxic effects of the combination, were investigated in 3 cancer cell lines to obtain insights into the involved mechanisms. Results: The optimal [177Lu]Lu-DOTA-trastuzumab activity when combined with Gd-NPs was 5 MBq. Moreover, compared with [177Lu]Lu-DOTA-trastuzumab alone, the strongest therapeutic efficacy (tumor mass reduction) was obtained with 2 injections of 5 mg of Gd-NPs/d (separated by 6 h) at 24 and 72 h after injection of 5 MBq of [177Lu]Lu-DOTA-trastuzumab. In vitro experiments showed that Gd-NPs colocalized with lysosomes and that their radiosensitizing effect was mediated by oxidative stress and inhibited by deferiprone, an iron chelator. Exposure of Gd-NPs to 177Lu increased the Auger electron yield but not the absorbed dose. Conclusion: Targeted radionuclide therapy can be combined with Gd-NPs to increase the therapeutic effect and reduce the injected activities. As Gd-NPs are already used in the clinic, this combination could be a new therapeutic approach for patients with ovarian peritoneal carcinomatosis.

Effects of Combination of Cisplatin and Paclitaxel Chemotherapy on Tumor Mass in Nasopharyngeal Carcinoma Patients at Dr. Wahidin Sudirohusodo Hospital Makassar with the RECIST Method

Background: Nasopharyngeal Carcinoma (NPC) is a malignant tumor that grows from epithelial cells that line the surface of the nasopharynx and has a tumor position close to the base of the skull, vital structures, and anatomical locations that are difficult to reach and various symptoms are the cause of increased patient mortality and morbidity rates. This research aims to identify the most effective chemotherapy effect on reducing tumor mass in nasopharyngeal cancer patients. Material and Methods: This study was conducted retrospectively based on patient medical record data from January 2019 to December 2021 at Dr. Wahidin Sudirohusodo General Hospital. Inclusion criteria included NPC patients who received cisplatin, carboplatin, paclitaxel, and docetaxel chemotherapy and had complete data on tumor mass size before and after receiving chemotherapy from Series I to Series VI. The resulting assessment of tumor mass size was further categorized using RECIST. Results: A total of 166 NPC patients met the inclusion criteria. The results of the study obtained that NPC patients suffered more in men than women, most NPC patients were aged (41-50), Stage IVA had the highest percentage found in NPC patients, Histopathology based on WHO type III was most commonly found in 109 patients, 70 patients used the Cisplatin+Paclitaxel chemotherapy regimen, 55 patients used the Cisplatin+Paclitaxel chemotherapy regimen had a partial tumor mass response. Conclusions: The combination of Cisplatin + Paclitaxel has the most partial response to the tumor mass of NPC patients at Wahidin Sudirohusodo General Hospital, Makassar.

Plasma Bacterial DNA Load as a Potential Biomarker for the Early Detection of Colorectal Cancer: A Case-Control Study.

The gut microbiota has gained increasing attention in recent years due to its significant impact on colorectal cancer (CRC) development and progression. The recent detection of bacterial DNA load in plasma holds promise as a potential non-invasive approach for early cancer detection. The aim of this study was to examine the quantity of bacterial DNA present in the plasma of 50 patients who have CRC in comparison to 40 neoplastic disease-free patients, as well as to determine if there is a correlation between the amount of plasma bacterial DNA and various clinical parameters. Plasma bacterial DNA levels were found to be elevated in the CRC group compared to the control group. As it emerged from the logistic analysis (adjusted for age and gender), these levels were strongly associated with the risk of CRC (OR = 1.02, p < 0.001, 95% C.I.: 1.01-1.03). Moreover, an association was identified between a reduction in tumor mass and the highest tertile of plasma bacterial DNA. Our findings indicate that individuals with CRC displayed a higher plasma bacterial DNA load compared to healthy controls. This observation lends support to the theory of heightened bacterial migration from the gastrointestinal tract to the bloodstream in CRC. Furthermore, our results establish a link between this phenomenon and the size of the tumor mass.

Ruthenium metallodendrimer against triple-negative breast cancer in mice

Carbosilane metallodendrimers, based on the arene Ru(II) complex (CRD13) and integrated to imino-pyridine surface groups have been investigated as an anticancer agent in a mouse model with triple-negative breast cancer. The dendrimer entered into the cells efficiently, and exhibited selective toxicity for 4T1 cells. In vivo investigations proved that a local injection of CRD13 caused a reduction of tumour mass and was non-toxic. ICP analyses indicated that Ru(II) accumulated in all tested tissues with a greater content detected in the tumour.

Targeting carcinoma-associated mesothelial cells with antibody-drug conjugates in ovarian carcinomatosis.

Ovarian carcinomatosis is characterized by the accumulation of carcinoma-associated mesothelial cells (CAMs) in the peritoneal stroma and mainly originates through a mesothelial-to-mesenchymal transition (MMT) process. MMT has been proposed as a therapeutic target for peritoneal metastasis. Most ovarian cancer (OC) patients present at diagnosis with peritoneal seeding, which makes tumor progression control difficult by MMT modulation. An alternative approach is to use antibody-drug conjugates (ADCs) targeted directly to attack CAMs. This strategy could represent the cornerstone of precision-based medicine for peritoneal carcinomatosis. Here, we performed complete transcriptome analyses of ascitic fluid-isolated CAMs in advanced OC patients with primary-, high-, and low-grade, serous subtypes and following neoadjuvant chemotherapy. Our findings suggest that both cancer biological aggressiveness and chemotherapy-induced tumor mass reduction reflect the MMT-associated changes that take place in the tumor surrounding microenvironment. Accordingly, MMT-related genes, including fibroblast activation protein (FAP), mannose receptor C type 2 (MRC2), interleukin-11 receptor alpha (IL11RA), myristoylated alanine-rich C-kinase substrate (MARCKS), and sulfatase-1 (SULF1), were identified as specific actionable targets in CAMs of OC patients, which is a crucial step in the de novo design of ADCs. These cell surface target receptors were also validated in peritoneal CAMs of colorectal cancer peritoneal implants, indicating that ADC-based treatment could extend to other abdominal tumors that show peritoneal colonization. As proof of concept, a FAP-targeted ADC reduced tumor growth in an OC xenograft mouse model with peritoneal metastasis-associated fibroblasts. In summary, we propose MMT as a potential source of ADC-based therapeutic targets for peritoneal carcinomatosis. © 2023 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

A remarkable and aggressive aneurysmal bone cyst ravaging the femoral shaft, advancing to lung metastases: An extremely rare case

Aneurysmal bone cysts (ABCs) are relatively uncommon tumor-like lesions that require careful management. Reporting such cases is crucial to highlight the importance of understanding the physiopathology and treatment options associated with ABCs. Literature-based writing emphasizes the significance of reporting cases like the one presented here. The aneurysmal bone cyst, classified as a Tumor Rich in Giant Cells according to the latest World Health Organization (WHO) classification of soft tissue and bone tumors, has posed several hypotheses and challenge. This aggressive form and rare localization of this lesion necessitates thorough discussions regarding its management.We present a compelling case of a 37-year-old patient, without any specific pathological history, with a giant diaphyseal aneurysmal bone cyst located in the right femur. Remarkably, the lesion had been progressing for a decade, leading to extensive destruction of the entire femoral diaphysis despite undergoing previous surgical interventions. The patient's unique circumstances highlight the unpredictable behavior and destructive potential of aneurysmal bone cysts in rare anatomical locations.This case underscores the need for a comprehensive understanding of aneurysmal bone cysts and their management. The utilization of denosumab, an inhibitor of the RANK/RANKL system, as a medical treatment in conjunction with surgery resulted in a favorable therapeutic response, including a reduction in tumor mass. The current WHO classification, recognizing ABCs as Tumors Rich in Giant Cells, consolidates previous hypotheses and enables the development of new therapeutic protocols. The integration of surgery and medical treatment holds promise for improving outcomes in patients with aneurysmal bone cysts. In conclusion, advancements in understanding the physiopathology and treatment options are crucial for developing effective therapeutic protocols to these aggressive forms of ABCs.

HOX Antisense Intergenic RNA Inhibitor Loaded on Magnetic Nanoparticles Inhibits Gastric Cancer Progression Through miR-20a-5p

Magnetic nanoparticles are easy to operate and highly efficient and acts as ideal molecular carriers. At the same time, research has found that inhibiting Homeotic Complex Gene transcript antisense RNA (HOTAIR) can inhibit tumor development. Therefore, this study intends to use magnetic nanoparticles to carry HOTAIR inhibitors to explore its role in gastric cancer progression. Magnetic nanoparticles loaded with HOTAIR inhibitor and mouse model of gastric cancer were constructed. Serum HOTAIR level was detected by ELISA, tumor volume and mass changes in mice were observed, and histopathology was assessed by HE staining. The effect of HOTAIR inhibitor loaded magnetic nanoparticles on miR-20a-5p expression and downstream apoptosis genes/proteins was also evaluated. (1) si-HOTAIR is the silent gene of HOTAIR. The obtained si-HOTAIR magnetic nanoparticles were used in various research groups. It was found that HOTAIR was highly expressed in gastric cancer mice. (2) HOTAIR inhibitor intervention reduced tumor mass and volume, and changed gastric histopathological conditions. (3) HOTAIR inhibitors inhibited the activities of gastric cancer MFC cells, promoted apoptosis, and downregulated miR-20a-5p. (4) Compared with other groups, miR-20a-5p in the cells of si-HOTAIR-loaded magnetic nanoparticles group was reduced and cancer progression was significantly inhibited. Magnetic nanoparticles loaded with HOTAIR inhibitors have a strong anti-tumor effect and this effect is achieved by inhibiting miR-20a-5p. At the same time, this process is related to Bcl-2.

Impact of endobiliary radiofrequency ablation on survival of patients with unresectable cholangiocarcinoma: a narrative review.

Cholangiocarcinoma (CCA) is a rare cancer originating from the biliary epithelium and accounts for about 3% of all gastrointestinal malignancies. Unfortunately, the majority of patients are not eligible for surgical resection at the time of diagnosis, because of the locally advanced stage or metastatic disease. The overall survival time of unresectable CCA is generally less than 1 year, despite current chemotherapy regimens. Biliary drainage is often required as a palliative treatment for patients with unresectable CCA. Recurrent jaundice and cholangitis tend to occur because of reobstruction of the biliary stents. This not only jeopardizes the efficacy of chemotherapy, but also causes significant morbidity and mortality. Effective control of tumor growth is crucial for prolonging stent patency and consequently patient survival. Recently, endobiliary radiofrequency ablation (ERFA) has been experimented as a treatment modality to reduce tumor mass, and delay tumor growth, extending stent patency. Ablation is accomplished by means of high-frequency alternating current which is released from the active electrode of an endobiliary probe placed in a biliary stricture. It has been shown that tumor necrosis releases intracellular particles which are highly immunogenic and activate antigen-presenting cells, enhancing local immunity directed against the tumor. This immunogenic response could potentially enhance tumor suppression and be responsible for improved survival of patients with unresectable CCA who undergo ERFA. Several studies have demonstrated that ERFA is associated with an increased median survival of approximately 6 months in patients with unresectable CCA. Furthermore, recent data support the hypothesis that ERFA could ameliorate the efficacy of chemotherapy administered to patients with unresectable CCA, without increasing the risk of complications. This narrative review discusses the results of the studies published in recent years and focuses on the impact that ERFA could have on overall survival of patients with unresectable cholangiocarcinoma.

Effects of Combination of Cisplatin and Paclitaxel Chemotherapy on Tumor Mass in Nasopharyngeal Carcinoma Patients at Dr. Wahidin Sudirohusodo Hospital Makassar with the RECIST Method

Background: Nasopharyngeal Carcinoma (NPC) is a malignant tumor that grows from epithelial cells that line the surface of the nasopharynx and has a tumor position close to the base of the skull, vital structures, and anatomical locations that are difficult to reach and various symptoms are the cause of increased patient mortality and morbidity rates. This research aims to identify the most effective chemotherapy effect on reducing tumor mass in nasopharyngeal cancer patients. Material and Methods: This study was conducted retrospectively based on patient medical record data from January 2019 to December 2021 at Dr. Wahidin Sudirohusodo General Hospital. Inclusion criteria included NPC patients who received cisplatin, carboplatin, paclitaxel, and docetaxel chemotherapy and had complete data on tumor mass size before and after receiving chemotherapy from Series I to Series VI. The resulting assessment of tumor mass size was further categorized using RECIST. Results: A total of 166 NPC patients met the inclusion criteria. The results of the study obtained that NPC patients suffered more in men than women, most NPC patients were aged (41-50), Stage IVA had the highest percentage found in NPC patients, Histopathology based on WHO type III was most commonly found in 109 patients, 70 patients used the Cisplatin+Paclitaxel chemotherapy regimen, 55 patients used the Cisplatin+Paclitaxel chemotherapy regimen had a partial tumor mass response. Conclusions: The combination of Cisplatin + Paclitaxel has the most partial response to the tumor mass of NPC patients at Wahidin Sudirohusodo General Hospital, Makassar.

Histidine Enhances the Anticancer Effect of Gemcitabine against Pancreatic Cancer via Disruption of Amino Acid Homeostasis and Oxidant-Antioxidant Balance.

Due to the severe toxicity posed by chemotherapeutic drugs, adjuvant nutritional intervention has gained increased attention in the treatment of pancreatic cancer (PC). Amino acid (AA) metabolism is aberrantly regulated in PC and circulating histidine (His) levels are low in PC patients. We hypothesized that His uptake and/or metabolism is dysregulated in PC and that combining His with gemcitabine (Gem), a drug used in the treatment of PC, will enhance the anti-cancer effects of Gem. We performed in vitro and in vivo studies to determine the anticancer effect of the combination of His and Gem against lethal PC. We demonstrate that circulating His levels are low in both human subjects and genetically engineered mice exhibiting pancreatic tumors. Interestingly, the expression of histidine ammonia lyase, an enzyme involved in His catabolism, is higher in PC compared to normal subjects. His + Gem exerts a more potent cytotoxic effect in PC cells compared to individual treatments. His treatment results in a profound increase in His accumulation, accompanied by a depletion of a number of AAs, promoting cancer cell survival and/or glutathione (GSH) synthesis. His but not Gem increases hydrogen peroxide and depletes cellular GSH. Supplementation with GSH protects cells against His + Gem-induced cytotoxicity. Further, our in vivo studies demonstrate that His + Gem potently reduced tumor mass and improved mouse survival. Taken together, our data suggest that PC cells exhibit an aberrant His uptake/accumulation which, in turn, leads to oxidative stress and depletion of AA pool, thereby enhancing the anticancer effect of Gem.

Pre-Operative Embolisation In Surgical Carotid Body Tumour Resection: Is It Really Useful?

Objective: Carotid body tumour (CBT) is the most common tumour in the family of head and neck paragangliomas, making up approximately 60 – 70% of them. They are typically diagnosed in the fourth to fifth decades with a female predilection. CBT present as soft tissue density on non-contrast CT and complete transfemoral angiography is considered the “gold standard” when establishing diagnosis of CBT with a 100% accuracy. Primary treatment consists of surgical resection to reduce tumour mass size and to decrease surgical risks associated with resection of these highly vascularised tumours, pre-operative embolisation of CBT has been proposed in the literature with varying results. There are no universal guidelines regarding pre-operative CBT embolisation and performance is mostly guided by preference of the surgeon and tumour size. The decision to perform pre-operative embolisation, usually 24 – 48 hours before surgery (though timing of surgical CBT resection following prior embolisation varies between 1 and 14 days post embolisation), is largely dependent on tumour size. Embolisation can be done via a transfemoral arterial route, or percutaneous (direct intralesional) route. The aim of this study was to investigate the efficacy of pre-operative embolisation prior to surgical CBT resection regarding intra-operative blood loss, operative time, length of hospital stay, and peri-operative complications (e.g., transient or ischaemic cerebrovascular event, vascular injury, or cranial nerve injury).

Abstract 367: The heparan sulfate mimetic PG545 inhibits tumor growth in both male and female mouse model of pancreatic ductal adenocarcinoma (PDAC) with sex difference in the effect on cachexia

Abstract BACKGROUND: Cachexia occurs in up to 80% of PDAC patients and is characterized by weight loss mainly due to muscle and fat wasting. Cachexia leads to functional impairment, reduced anticancer therapy tolerance and increased mortality. PG545, a heparan sulfate (HS) mimetic, shows anticancer activity; however, it is unknown whether sex affects the anticancer activity and what effect PG545 has on cancer associated muscle and fat wasting. Given that many cytokines induced in patients with cancer cachexia can bind HS, the aim of this study was to assess PG545 effects on PDAC cachexia with emphasis on sex difference. METHODS: PDAC cells were injected into the pancreas of 10-week C57BL/6 male and female mice. The orthotopic tumor-bearing mice were treated with PG545 (10 mg/kg; i.p.). Body weight and body composition were monitored, and tumor and organs were collected. Skeletal muscles were cryosectioned for evaluation of cross-sectional area (CSA). C2C12 myotubes, the in vitro model of muscle wasting, were treated with PDAC cell-derived conditioned medium (CM) without or with PG545 and analyzed for the changes in size. PDAC cell proliferation was assessed by MTT assay. RESULTS: PG545 treatment markedly reduced tumor mass in both males and females compared to the vehicle controls. PG545 also reduced body weight but the difference gradually dissipated over time despite repeated dosing. However, male mice recovered from the negative effects more slowly than female mice. Similar sex difference was observed in the changes in the PG545-induced lean and fat mass loss. Of note, fat mass in PG545-treated females at the end of experiment was higher than in the vehicle controls. Furthermore, males had more reductions in muscle and fat weights than females in response to PG545. Grip strength in males was weakened by PG545 but returned to the level like that in the vehicle controls at the end, while PG545 did not weaken grip strength in females at the same time points. In addition, males, but not females, had smaller muscle fiber CSA after PG545 treatment versus their vehicle controls. In in vitro assay, PG545 inhibited PDAC cell proliferation, indicating a direct effect on cancer cells. Lastly, opposed to the in vivo effect, PG545 partly prevented myotube wasting induced by PDAC CM. CONCLUSION: PG545 has strong anti-PDAC activity in both male and female mice, at least partly through inhibition of cancer cell proliferation. Its initial negative effects on cachexia are gradually reversed with male tumor-bearing mice reversing more slowly than females. Because of the protective effect on C2C12 myotubes treated with PDAC CM, PG545 might induce some counteracting factors in vivo in the initial treatment and identification of these factors may offer molecular targets for combination therapy to counteract the negative effects while take advantage of the strong anti-cancer potential. Citation Format: Xiaoling Zhong, Keith Dredge, John M. Chirgwin, Michael G. House, Harikrishna Nakshatri, Teresa A. Zimmers. The heparan sulfate mimetic PG545 inhibits tumor growth in both male and female mouse model of pancreatic ductal adenocarcinoma (PDAC) with sex difference in the effect on cachexia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 367.

Novel bis-amide-based bis-thiazoles as Anti-colorectal Cancer Agents Through Bcl-2 Inhibition: Synthesis, In Vitro, and In Vivo studies.

Some heterocycles having bisamide linkage are receiving much interest due to their remarkable biological potencies and they are naturally occurring. Some bisamides and thiazole derivatives were found to inhibit the protein levels of Bcl-2 significantly. This prompted us to synthesize new bis(heterocyclic) derivatives having bisamide function to explore their anti-cancer activities. Novel bis-amide-based bis-thiazoles and thiadiazoles were synthesized by reaction of a new bisthiosemicarbazone with a variety of hydrazonoyl chlorides, a-chloroacetylacetone and haloacetic acid derivatives. Most of the synthesized derivatives were tested for colorectal (HCT-116) and breast (MCF-7) cell lines using the MTT assay, with the apoptotic investigation through flow cytometric and RT-PCR analyses. Some derivatives were found to be highly cytotoxic against HCT-116 cells with an IC50 range of (10.44-13.76 μM) compared to 5-fluorouracil (5-FU) (IC50 = 11.78 μM). One product significantly stimulated apoptotic colorectal cancer cell death by 27.24-fold (50.13% compared to control 1.84%) by arresting the cell cycle at the G2/M phase. The obtained results revealed that compound 7f was more cytotoxic against HCT-116 cells than 5-FU. Compound 7f remarkably enhanced apoptotic colorectal cancer cell death and upregulated the propapoptotic genes (P53, BAX and Capases-3,-8,-9) and downregulated the anti-apoptotic gene, B-cell lymphoma 2 (Bcl-2). In vivo study exhibited that 7f-treatment caused tumor inhibition ratio (TIR%) of 50.45% compared to 54.86% in the 5-FU treatment, with a significant reduction in tumor mass and volume. The anti-tumor activity of compound 7f was accompanied by ameliorated hematological and biochemical analyses, histopathological improvement in treated liver tissues, and the immunohistochemical staining revealed Bcl-2 inhibition in agreement with the in vitro results. Compound 7f is an interesting candidate for further development as a chemotherapeutic anti-cancer agent.

Shenqi Fuzheng injection reverses M2 macrophage-mediated cisplatin resistance through the PI3K pathway in breast cancer.

Shenqi Fuzheng injection (SQFZ) combined with chemotherapy can sensitize tumour cells. However, the mechanisms underlying SQFZ's effects remain unknown. In human breast cancer cell lines and M2 macrophages, we showed that SQFZ was a significantly potent agent of sensitization. The human breast cancer cell line, MDA-MB-231/DDP, and the human acute leukaemia mononuclear cell line, THP-1, were used. MDA-MB-231/DDP breast cancer xenografts were established to monitor tumour growth. Resistance-associated proteins were examined by western blotting. Levels of cytokines and chemokines were detected by ELISA. Cell viability was measured using the MTT assay. Apoptosis was detected by flow cytometric analysis. SQFZ significantly enhanced the capability of cisplatin to reduce tumour mass. SQFZ and cisplatin decreased the expression of CD206 by 1.89-fold and increased that of CD86 by 1.76-fold as compared to cisplatin alone. The levels of PGE2, IL-6, and CCL1 decreased significantly, and the activation of p-PI3K and the expressions of P-gp and ABCG2 were also inhibited by SQFZ in combination with cisplatin treatment in vivo. The survival following cisplatin administration of 60 μM and 120 μM reduced significantly in the presence of SQFZ in MDA-MB-231/DDP and M2 co-cultured cells. IGF-1, a PI3K activator, combined with SQFZ weakened the effects of SQFZ-induced apoptosis from 28.7% to 10.5%. The effects of IGF-1 on increasing the expressions of P-gp, ABCG2, and Bcl-2, and decreasing that of Bax were reversed by SQFZ. Our findings provide evidence that SQFZ is a potential therapeutic drug for cancer therapy.

Effect of the mycotoxin deoxynivalenol in combinational therapy with TRAIL on prostate cancer cells

Tumor necrosis factor-related apoptosis-induced ligand (TRAIL) is reported as a promising anti-cancer therapeutic target. Unfortunately, prostate cancer cells (PCa) are partially resistant to TRAIL-induced apoptosis limiting its therapeutic potential. The existing body of knowledge suggests that naturally produced compounds, such as mycotoxin deoxynivalenol (DON), might potentially sensitize cells to TRAIL treatment and improve the efficiency of therapy. Previously, we observed that DON induces oxidative stress and apoptosis in PCa cell lines. Thus we addressed here whether DON can sensitize PCa cells to TRAIL-induced apoptosis. Our data demonstrates that three out of four tested PCa cell lines pretreated with DON increased TRAIL-induced apoptosis detected with flow cytometry. This effect was associated with oxidative stress (LNCaP and DU-145 cell line) and elevated DNA damage (DU-145, LNCaP, and 22Rv1 cell lines). Next, in the animal model we inoculated PC tumor to SCKID mice followed by administration of DON intraperitoneally and/or TRIAL intravenously. During 21 days monitoring of tumor growth, the animals received 7 doses of DON, TRAIL, DON+TRAIL or control injections. No significant reduction in tumor mass was observed after combinational treatment of TRAIL and DON compared to 1 μg/kg of body weight DON treatment alone, which itself decreased the tumor growth. However, despite the lack of the TRAIL + DON effect, DON itself inducing apoptosis is an interesting compound worth investigating in the context of other combination therapies.

Abstract IA046: Mechanistic targets and strategies to break the obesity-cancer link

Abstract Obesity promotes the incidence and progression of many cancers including breast cancer. Mechanisms underpinning obesity-driven breast cancer that could be harnessed to intercept this deleterious relationship are not completely understood. Here we apply multi-omics analysis of tumor and adipose to delineate candidate mediators underlying the procancer effects of obesity, and anticancer effects of weight loss, in a mouse model of obesity-driven breast cancer. We modeled bariatric surgery and nonsurgical weight loss in obese C57BL/6NCrl mice fed a high-fat diet (60 kcal% fat) using vertical sleeve gastrectomy or a sham surgery paired with (i) dietary weight loss via ad libitum low-fat diet (10 kcal% fat), (ii) 30% chronic calorie restriction, or (iii) intermittent calorie restriction. Once weight loss stabilized, mammary tumors were induced by orthotopic transplantation of E0771 cells, a model of triple negative breast cancer (TNBC). While bariatric surgery and a switch to low-fat diet were each moderately effective at reducing tumor mass, chronic and intermittent calorie restriction regimens were each highly effective in reducing tumor burden. Tumor transcriptomic analysis using gene set enrichment analysis revealed that weight loss interventions reversed obesity-associated immunosuppression. Mediation analysis identified weight loss and fat mass loss as significant mediators of the reduced tumor mass seen in all interventions. Integration of adipose transcriptomics and reduced-representation bisulfite sequencing identified NFKB1, FXR1, and BACH1 as regulators overrepresented in differentially methylated genes, and conserved with predicted regulators of transcriptional remodeling in human adipose tissue following bariatric surgery. These data indicate that weight loss through dietary and surgical means promotes antitumor immunity, in part via remodeling of tumor adjacent adipose tissue. We have identified several candidate mediators of adipose remodeling that may underpin the antitumor effects of bariatric surgery, and these mediators represent potential mechanism-based targets for future interventions. Citation Format: Michael F. Coleman. Mechanistic targets and strategies to break the obesity-cancer link [abstract]. In: Proceedings of the 15th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2022 Sep 16-19; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2022;31(1 Suppl):Abstract nr IA046.

Oxymatrine Inhibits Malignant Behaviors of Breast Cancer Cells by Inhibiting miR-188 Expression to Up-Regulate Phosphatase and Tensin Homolog (PTEN)

Oxymatrine has been applied to anti-cancer therapies for various cancers. The present study aimed to investigate the potential impact of miR-188 on breast cancer (BC) cell progression and underlying mechanism. After establishment of a rat model of BC, rats were administered with oxymatrine (4 mg/kg, 8 mg/kg), Xihuang pill (XH) (positive control), and miR-188 mimic (1 mg/kg) followed by analysis of tumor growth, the expression of miR-188, MMP-9, MMP-2, and PTEN, and BC cell behaviors. Oxymatrine significantly decreased tumor incidence and reduced tumor mass (p&lt;0.05) with 8 mg/kg intervention group and positive control group exhibiting higher tumor inhibition rate (p&lt;0.05). In addition, oxymatrine or XH effectively reduced cell proliferation, invasion and migration rate. Of note, compared to 4 mg/kg oxymatrine, 8 mg/kg oxymatrine and XH showed more significantly inhibitory effects on BC cells. Moreover, oxymatrine or XH significantly downregulated miR-188, MMP-9, and MMP-2 and upregulated PTEN. Mechanically, PTEN was indicated as the target of miR-188 with specific binding between them. In conclusion, Oxymatrine inhibits BC cell behaviors through down-regulation of miR-188 to increase PTEN expression. This study might provide a new basis for the management of BC.

PS-R03-4: TRANSARTERIAL EMBOLIZATION, THORACIC SPINE DECOMPRESSION AND FUSION OF METASTATIC PHEOCHROMOCYTOMA: A CASE REPORT

Surveillance of metastatic lesions and biochemical control of catecholamines in patients with malignant pheochromocytoma remain a fundamental problem to be solved. Here we present a 60-year-old male who visited a local clinic because of headache, sweating, malaise, and loss of body weight. Hypertension, orthostatic hypotension, along with remarkable increase in serum and urine noradrenaline, and urine metanephrine and vanillylmandelic acid were noted, and pheochromocytoma was suspected accordingly. Magnetic resonance imaging failed to reveal adrenal gland or sympathetic plexuses, yet it uncovered metastatic lesions in the liver and spine. Functional imaging study using 131I-Metaiodobenzylguanidine (MIBG) scan detected notable uptake in the spinal lesion, albeit not in the hepatic lesion. On the other hand, positron emission tomography with fluorodeoxyglucose (FDG-PET) disclosed FDG uptake both in the hepatic and spinal masses. Biopsy of the hepatic tumors revealed chromogranin A-positive clusters of cells, a finding consistent with metastatic pheochromocytoma. Transarterial embolization (TAE) of the metastatic tumors in the liver was performed for the purpose of tumor mass reduction. Additionally, TAE followed by resection of the spinal lesion was conducted. Pathological examination of the spinal tumor also showed chromogranin A-positive cells, leading to diagnosis of malignant pheochromocytoma. Crucially, TAE of the liver and spinal tumors resulted in dramatic reduction of catecholamine production, likely constituting an effective therapeutic strategy against metastatic pheochromocytoma (Homma, et al. Hypertens Res 2006). Afterwards, the patient became unable to walk because of weakness in the left leg at the age of 64. It seemed attributed to spinal cord compression from the tumor at the level of thoracic vertebrae 7. The patient underwent posterior decompression and fusion, and his muscle strength of the left leg was recovered. At the age of 65, the patient developed paralytic ileus following a surgery against metastatic tumors in the skull. In this case report, we discuss early detection of metastatic lesions and biochemical control of catecholamines in patients with malignant pheochromocytoma.

Low Sulfur Amino Acid, High Polyunsaturated Fatty Acid Diet Inhibits Breast Cancer Growth

Cancer cells may acquire resistance to stress signals and reprogram metabolism to meet the energetic demands to support their high proliferation rate and avoid death. Hence, targeting nutrient dependencies of cancer cells has been suggested as a promising anti-cancer strategy. We explored the possibility of killing breast cancer (BC) cells by modifying nutrient availability. We used in vitro models of BC (MCF7 and MDA-MB-231) that were maintained with a low amount of sulfur amino acids (SAAs) and a high amount of oxidizable polyunsatured fatty acids (PUFAs). Treatment with anti-apoptotic, anti-ferroptotic and antioxidant drugs were used to determine the modality of cell death. We reproduced these conditions in vivo by feeding BC-bearing mice with a diet poor in proteins and SAAs and rich in PUFAs (LSAA/HPUFA). Western blot analysis, qPCR and histological analyses were used to assess the anti-cancer effects and the molecular pathways involved. We found that BC cells underwent oxidative damage to DNA and proteins and both apoptosis and ferroptosis were induced. Along with caspases-mediated PARP1 cleavage, we found a lowering of the GSH-GPX4 system and an increase of lipid peroxides. A LSAA/HPUFA diet reduced tumor mass and its vascularization and immune cell infiltration, and induced apoptosis and ferroptotic hallmarks. Furthermore, mitochondrial mass was found to be increased, and the buffering of mitochondrial reactive oxygen species limited GPX4 reduction and DNA damage. Our results suggest that administration of custom diets, targeting the dependency of cancer cells on certain nutrients, can represent a promising complementary option for anti-cancer therapy.

Yttrium-90 transarterial radioembolization for liver metastases from medullary thyroid cancer.

Liver metastases occur in 45% of patients with advanced metastatic medullary thyroid cancer (MTC). Transarterial radioembolization (TARE) has been proposed to treat liver metastases (LM), especially in neuroendocrine tumors. The aim of this study was to investigate the biochemical (calcitonin and carcino-embryonic antigen) and objective response of liver metastases from MTC to TARE. TARE is an internal radiotherapy in which microspheres loaded with β-emitting yttrium-90 (90Y) are delivered into the hepatic arteries that supply blood to LM. Eight patients with progressive multiple LM underwent TARE and were followed prospectively. They were clinically, biochemically and radiologically evaluated at 1, 4, 12 and 18 months after TARE. Two patients were excluded from the analysis due to severe liver injury and death due to extrahepatic disease progression, respectively. One month after TARE, a statistically significant (P = 0.02) reduction of calcitonin was observed in all patients and remained clinically relevant during follow-up; reduction of CEA, although not significant, was found in all patients. Significant reduction of liver tumor mass was observed 1, 4 and 12 months after TARE (P = 0.007, P = 0.004, P = 0.002, respectively). After 1 month, three of six patients showed partial response (PR) and three of six stable disease (SD) according to RECIST 1.1, while five of six patients had a PR and one of six a SD according to mRECIST. The clinical response remained relevant 18 months after TARE. Excluding one patient, all others showed only a slight and transient increase in liver enzymes. TARE is effective in LM treatment of MTC. The absence of severe complications and the good tolerability make TARE a valid therapeutic strategy when liver LM are multiple and progressive.