Cancer Death In Men Research Articles

Fibroblast-derived conditioned media promotes lung cancer progression

Lung cancer is the leading cause of cancer death in men and women in the United States. Recent studies have implicated the tumor microenvironment as a new chemotherapeutic target by demonstrating the importance of tumor cell-stromal interactions in cancer progression. However, the exact mechanisms by which tumor cell-stromal interactions drive lung cancer progression remain undefined, particularly in the lung. We suspect host fibroblasts represent an important component of the tumor microenvironment that drives tumor progression. We found that human non-small cell lung carcinoma cell lines show alterations in cell morphology, proliferation, migration, and colony formation on soft agar when exposed to fibroblast-conditioned media (FCM). Interestingly, FCM also promoted tumor cell resistance to cisplatin-induced apoptosis. These effects varied depending on the cancer cell line used. Similar observations were made when exposing murine Lewis Lung Carcinoma cells to conditioned media harvested from primary murine lung fibroblasts. Certain effects of FCM, but not all, could be prevented by using a cMET inhibitor. In vivo, we observed enhanced growth of the primary tumors when treated with FCM, but no changes in metastatic behavior. Although the identity of the stimulating agent(s) in the fibroblast-conditioned media was not unveiled, further studies revealed that the activity is more than one factor with a high-molecular weight (over 100 kDa). These studies implicate lung fibroblast-derived factors in lung cancer progression. These data suggest that targeting the lung tumor stroma alone, or in combination with other interventions, is a promising concept that warrants further study in the setting of lung cancer.

Attributable fraction of tobacco smoking on selected cancer deaths in the past decade using mortality case-control study in Tianjin, China.

INTRODUCTIONThis study aims to estimate the impact of smoking-attributable mortality of selected cancers, in the period 2010–2019 in Tianjin, China.METHODSA case-control study was conducted to assess the smoking-attributed major causes of cancer deaths. Unmatched multiple logistic regression was used to calculate mortality risk ratios.RESULTSSmoking-attributable cancer deaths were 23709 (28.87%) among adult males and 8648 (13.37%) among adult females in the period 2010–2019 in Tianjin, China. Lung cancer remains the largest cause of smoking-attributable deaths; among men, the death rates were 49.06% of lung cancers, 27.55% of mouth, pharynx, larynx, or esophagus cancers, 13.56% of kidney and other urinary cancers, and 10.11% of liver cancers; among women the corresponding death rates were 31.56% of lung cancers and 10.59% of the mouth, pharynx, larynx, or esophagus cancer, 10.56% of bladder cancers. Smoking-attributed cancer deaths in men increased from 1817 in 2010 to 2695 in 2019; for women, the number remained stable at just over 800 per year during the past decade.CONCLUSIONSAt least one in three cancer deaths in men and one in six in women would be potentially preventable through appropriate control of tobacco smoking in Tianjin, China. Effective control programs against tobacco smoking should be further implemented.

An Efficient Deep Learning Approach for Colon Cancer Detection

Colon cancer is the second most common cause of cancer death in women and the third most common cause of cancer death in men. Therefore, early detection of this cancer can lead to lower infection and death rates. In this research, we propose a new lightweight deep learning approach based on a Convolutional Neural Network (CNN) for efficient colon cancer detection. In our method, the input histopathological images are normalized before feeding them into our CNN model, and then colon cancer detection is performed. The efficiency of the proposed system is analyzed with publicly available histopathological images database and compared with the state-of-the-art existing methods for colon cancer detection. The result analysis demonstrates that the proposed deep model for colon cancer detection provides a higher accuracy of 99.50%, which is considered the best accuracy compared with the majority of other deep learning approaches. Because of this high result, the proposed approach is computationally efficient.

Therapeutic Potential of Marine Peptides in Prostate Cancer: Mechanistic Insights.

Prostate cancer (PCa) is the leading cause of cancer death in men, and its treatment is commonly associated with severe adverse effects. Thus, new treatment modalities are required. In this context, natural compounds have been widely explored for their anti-PCa properties. Aquatic organisms contain numerous potential medications. Anticancer peptides are less toxic to normal cells and provide an efficacious treatment approach via multiple mechanisms, including altered cell viability, apoptosis, cell migration/invasion, suppression of angiogenesis and microtubule balance disturbances. This review sheds light on marine peptides as efficacious and safe therapeutic agents for PCa.

Chronic nitric oxide exposure induces prostate cell carcinogenesis, involving genetic instability and a pro-tumorigenic secretory phenotype

Prostate cancer is a leading cause of cancer death in men. Inflammation and overexpression of inducible nitric oxide synthase (NOS2) have been implicated in prostate carcinogenesis. We aimed to explore the hypothesis that nitric oxide NO exerts pro-tumorigenic effects on prostate cells at physiologically relevant levels contributing to carcinogenesis. We investigated the impact of acute exposure of normal immortalised prostate cells (RWPE-1) to NO on cell proliferation and activation of DNA damage repair pathways. Furthermore we investigated the long term effects of chronic NO exposure on RWPE-1 cell migration and invasion potential and hallmarks of transformation. Our results demonstrate that NO induces DNA damage as indicated by γH2AX foci and p53 activation resulting in a G1/S phase block and activation of 53BP1 DNA damage repair protein. Long term adaption to NO results in increased migration and invasion potential, acquisition of anchorage independent growth and increased resistance to chemotherapy. This was recapitulated in PC3 and DU145 prostate cancer cells which upon chronic exposure to NO displayed increased cell migration, colony formation and increased resistance to chemotherapeutics. These findings indicate that NO may play a key role in the development of prostate cancer and the acquisition of an aggressive metastatic phenotype.

The prostate tissue-based telomere biomarker as a prognostic tool for metastasis and death from prostate cancer after prostatectomy.

Current biomarkers are inadequate prognostic predictors in localized prostate cancer making treatment decision‐making challenging. Previously, we observed that the combination of more variable telomere length among prostate cancer cells and shorter telomere length in prostate cancer‐associated stromal cells – the telomere biomarker – is strongly associated with progression to metastasis and prostate cancer death after prostatectomy independent of currently used pathologic indicators. Here, we optimized our method allowing for semi‐automated telomere length determination in single cells in fixed tissue, and tested the telomere biomarker in five cohort studies of men surgically treated for clinically localized disease (N = 2,255). We estimated the relative risk (RR) of progression to metastasis (N = 311) and prostate cancer death (N = 85) using models appropriate to each study's design adjusting for age, prostatectomy stage, and tumor grade, which then we meta‐analyzed using inverse variance weights. Compared with men who had less variable telomere length among prostate cancer cells and longer telomere length in prostate cancer‐associated stromal cells, men with the combination of more variable and shorter telomere length had 3.76 times the risk of prostate cancer death (95% confidence interval [CI] 1.37–10.3, p = 0.01) and had 2.23 times the risk of progression to metastasis (95% CI 0.99–5.02, p = 0.05). The telomere biomarker was associated with prostate cancer death in men with intermediate risk disease (grade groups 2/3: RR = 9.18, 95% CI 1.14–74.0, p = 0.037) and with PTEN protein intact tumors (RR = 6.74, 95% CI 1.46–37.6, p = 0.015). In summary, the telomere biomarker is robust and associated with poor outcome independent of current pathologic indicators in surgically treated men.

A Web-Based Prediction Model for Cancer-Specific Survival of Elderly Patients Undergoing Surgery With Prostate Cancer: A Population-Based Study.

ObjectiveProstate cancer (PC) is the second leading cause of cancer death in men in the United States after lung cancer in global incidence. Elderly male patients over 65 years old account for more than 60% of PC patients, and the impact of surgical treatment on the prognosis of PC patients is controversial. Moreover, there are currently no predictive models that can predict the prognosis of elderly PC patients undergoing surgical treatment. Therefore, we aimed to construct a new nomogram to predict cancer-specific survival (CSS) in elderly PC patients undergoing surgical treatment.MethodsData for surgically treated PC patients aged 65 years and older were obtained from the Surveillance, Epidemiology, and End Results (SEER) database. Univariate and multivariate Cox regression models were used to identify independent risk factors for elderly PC patients undergoing surgical treatment. A nomogram of elderly PC patients undergoing surgical treatment was developed based on the multivariate Cox regression model. The consistency index (C-index), the area under the subject operating characteristic curve (AUC), and the calibration curve were used to test the accuracy and discrimination of the predictive model. Decision curve analysis (DCA) was used to examine the potential clinical value of this model.ResultsA total of 44,975 elderly PC patients undergoing surgery in 2010–2018 were randomly assigned to the training set (N = 31705) and validation set (N = 13270). the training set was used for nomogram development and the validation set was used for internal validation. Univariate and multivariate Cox regression model analysis showed that age, marriage, TNM stage, surgical style, chemotherapy, radiotherapy, Gleason score(GS), and prostate-specific antigen(PSA) were independent risk factors for CSS in elderly PC patients undergoing surgical treatment. The C index of the training set and validation indices are 0.911(95%CI: 0.899–0.923) and 0.913(95%CI: 0.893–0.933), respectively, indicating that the nomogram has a good discrimination ability. The AUC and the calibration curves also show good accuracy and discriminability.ConclusionsTo our knowledge, our nomogram is the first predictive model for elderly PC patients undergoing surgical treatment, filling the gap in current predictive models for this PC patient population. Our data comes from the SEER database, which is trustworthy and reliable. Moreover, our model has been internally validated in the validation set using the C-index,AUC and the and the calibration curve, showed that the model have good accuracy and reliability, which can help clinicians and patients make better clinical decision-making. Moreover, the DCA results show that our nomogram has a better potential clinical application value than the TNM staging system.

AMPK's double-faced role in advanced stages of prostate cancer.

Prostate cancer (PCa) is the second leading cause of cancer deaths in men. Unfortunately, a very limited number of drugs are available for the relapsed and advanced stages of PCa, adding only a few months to survival; therefore, it is vital to develop new drugs. 5´ AMP-activated protein kinase (AMPK) is a master regulator of cell metabolism. It plays a significant role in the metabolism of PCa; hence, it can serve well as a treatment option for the advanced stages of PCa. However, whether this pathway contributes to cancer cell survival or death remains unknown. The present study reviews the possible pathways by which AMPK plays role in the advanced stages of PCa, drug resistance, and metastasis: (1) AMPK has a contradictory role in promoting glycolysis and the Warburg effect which are correlated with cancer stem cells (CSCs) survival and advanced PCa. It exerts its effect by interacting with hypoxia-induced factor 1 (HIF1) α, pyruvate kinase 2 (PKM2), glucose transporter (GLUT) 1 and pyruvate dehydrogenase complex (PDHC), which are key regulators of glycolysis; however, whether it promotes or discourage glycolysis is not conclusive. It can also exert an anti-CSC effect by negative regulation of NANOG and epithelial-mesenchymal transition (EMT) transcription factors, which are the major drivers of CSC maintenance; (2) the regulatory effect of AMPK on autophagy is also noticeable. Androgen receptors' expression increases AMPK activation through Calcium/calmodulin-dependent protein kinase 2 (CaMKK2) and induces autophagy. In addition, AMPK itself increases autophagy by downregulating the mammalian target of rapamycin complex (mTORC). However, whether increased autophagy inhibits or promotes cell death and drug resistance is contradictory. This study reveals that there are numerous pathways other than cell metabolism by which AMPK exerts its effects in the advanced stages of PCa, making it a priceless treatment target. Finally, we mention some drugs developed to treat the advanced stages of PCa by acting on AMPK.

Prostate Cancer Classification Using Artificial Neural Networks

Prostate cancer is one of the major causes of cancer death in men in the Western world. One in 6 men will develop prostate cancer in his lifetime. Early detection and accurate diagnosis of the disease can improve cancer survival and reduce treatment costs [Computer-aided detection of prostate cancer in MRI. IEEE, May 2014]. The artificial neural network (ANN) is used to classify and extract the feature of the magnetic resonance imaging (MRI) scan. This classification is computer-based and has the advantage that it enriches the patient from the doctor and undergoes the different diagnostic techniques that may appear to be stressful and painful. A computer-aided classification set of MRI scans of the prostate subjects these images to a set of preprocessing and image enhancement giving an accurate classification to improve the properties of the image such as noise filtering to improve the contrast of the image and then using segmentation to separate the tumor region and feature extraction; this step can be done by using a set of rolls (explained below). This feature is used to input data to ANN. It classifies the given data set into benign or malignant (prostate cancer). The system succeeded in classifying malignant tumors with 92.4%, increasing decision-making and providing particular treatment. The computerized method detects the tumor in its early stage; thus, good classification is an essential part. The first stage is to extract features from MRI using principal component analysis (computer aided diagnosis), and the second stage is to train the probabilistic neural network (ANN) for classification. The computer aided diagnosis method gives existing attributes a new set of calculated parameters.

PCR139 The Role of Patient Engagement in the Adoption and Use of a Mobile Application (HEALTH STORYLINES) Among Men with Prostate Cancer

Prostate cancer is the second leading cause of cancer death in men in the United States. Digital health tools have been developed to capture the experience of patients and facilitate personalized treatment, however men are less likely to engage in consistent self-monitoring compared to women. This research evaluated the use of a mobile health app Health Storylines to capture data relevant to patient experience and treatment effectiveness among men diagnosed with prostate cancer, and the impact of collaboration with a patient advocacy partner in educating patients on the value of using the app to support their treatment journey.

Abstract LB053: PDAC derived exosomes manipulate tumor pericyte phenotype

Abstract Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer death in men and women in the U.S., with a 5-year survival rate of 10%. This poor prognosis is partly due to the aggressive nature of the disease, lack of early detection methods, its complex and dense tumor microenvironment (TME), and lack of effective treatment options. Within the PDAC TME, morphologically aberrant leaky vessels are responsible for hypoxia and impaired immune response, which likely reduces the efficacy of cancer therapies. We and others showed that pericyte coverage significantly correlates with vascular integrity/function and intratumoral hypoxia. Therefore, understanding perivascular heterogeneity and the unique contribution of each phenotype to the TME evolution is a critical step towards personalized treatment options for PDAC. Our study revealed that tumor-associated pericytes across all PDAC tumor tissues exhibited ectopic αSMA expression up to 10X higher compared to the normal pericytes. This aberrant pericyte phenotype was correlated with vascular leakiness and hypoxia, whereas the Des+ mature pericyte phenotype was inversely correlated with vessel leakiness. Our attempt to elucidate the underlying mechanism of pericyte phenotype switching using in vitro culture system shows that pancreatic cancer cell-derived extracellular vesicles (PC-Exo) is a potent inducer of αSMA expression in pericyte. PC-Exo was also sufficient enough to induce αSMA expression in normal pericytes within the pancreas when injected into the WT mice. In addition to the changes in pericyte markers, PC-Exo stimulated pericytes exhibited immunomodulatory phenotype with significantly higher expression of HLA-DRA, CD274, CD80, E-selectin, and P-selectin. Considering αSMA is a cytoskeletal protein that can influence cellular stiffness, migration, and downstream signaling, we also examined the biomechanical properties of pericytes with altered phenotype. The results show a significant increase in pericyte stiffness and cellular height of aSMA+ pericyte. These pericytes also have elongated morphology and cytoskeletal reorganization visualized by αSMA and phalloidin immunostaining. A recent study showed that acquired αSMA expression converts capillary pericytes into contractile vascular smooth muscle-like cells. Blood vessels are constricted and collapsed within the PDAC TME, which may be partly caused by an abundance of αSMA+ pericytes. In conclusion, our study indicates that tumor-associated pericytes undergo phenotype switching under the influence of pancreatic cancer cells, and these aberrant pericytes might contribute to non-optimal vascular integrity/function. Together, our study indicates that tumor conditioned αSMA+ pericytes present mechanical abnormalities and immune-suppressive features. Future work includes exploring the vascular normalization approach by suppressing pericyte phenotype switching to enhance vascular function and chemo- and immunotherapeutic efficacy. Citation Format: Vikneshwari Natarajan, Alexander Delgado, Reed Jacobson, Lina Alhalhooly, Yongki Choi, Sangdeuk Ha, Jiha Kim. PDAC derived exosomes manipulate tumor pericyte phenotype [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr LB053.

Abstract 5822: Leptin modulated microRNA-628-5p targets Jagged1 and inhibits prostate cancer hallmarks

Abstract Prostate cancer (PCa) is the most commonly diagnosed non-cutaneous cancer and the second leading cause of cancer deaths in men. Obesity is a major risk factor for prostate cancer. Leptin is an obesity hormone that controls body weight by regulating energy intake and expenditure, and clinical studies have demonstrated a correlation between blood leptin levels and PCa development. MicroRNAs (miRs) are master regulators of cancer cell signaling, including in advanced PCa. We previously identified miR-628-5p as a potential biomarker in PCa patients that was downregulated in serum samples of men with PCa (Tumor Biol., 2014, 35: 4867). In this study, we investigated the link between the obesity hormone leptin and the functional role of miR-628-5p in PCa cell lines. We demonstrate that leptin downregulates the expression of miR-628-5p and increases cell proliferation and migration in PCa cells. Enforced expression of miR-628-5p inhibited cell proliferation in PCa cells. Further, miR-628-5p reduced PCa cell survival/migration/invasion/spheroids formation and cell stemness. Mechanistically, miR-628-5p binds with JAG1-3’UTR and inhibits the expression of Jagged-1 (JAG1). JAG1 inhibition by miR-628-5p also downregulated Notch signaling, decreased the expression of snail/slug, and modulated epithelial-mesenchymal transition and invasiveness in PC3 cells. Furthermore, miR-628-5p increased sensitivity towards enzalutamide and docetaxel by inducing cell apoptosis. Collectively our data suggested that miR-628-5p is a key regulator of PCa carcinogenesis modulated by adipokine leptin and offers a novel therapeutic opportunity to inhibit the growth of advanced PCa. Citation Format: Leslimar Rios Colon, Juliet Chijioke, Suryakant Niture, Zainab Afzal, Qi Qi, Anvesha Srivastava, Malathi Ramalinga, Habib Kedir, Patrice Cagle, Elena Arthur, Gagan Deep, Simeng Suy, Sean Collins, Deepak Kumar. Leptin modulated microRNA-628-5p targets Jagged1 and inhibits prostate cancer hallmarks [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5822.

Abstract 7: A Colorectal Biomarker Think Tank Collaborative: Devising Solutions for Patients, Caregivers, and Cancer Care Teams

Abstract Background: Colorectal cancer is the third-most commonly diagnosed cancer and the second-leading cause of cancer death in men and women combined in the United States. With more than a dozen known mutations in colorectal cancer, and growing knowledge about different efficacy of drug options dependent on biomarker status, biomarker testing and results can aid in more effective and lifesaving treatment planning specifically for the unique characteristics of each individual’s tumor. However, biomarker testing in colorectal cancer remains low, and the Colorectal Cancer Alliance aims to increase knowledge and awareness of testing among patients and their care teams. Methods: In 2019, the Alliance conducted an online survey to assess patient, survivor, and caregiver knowledge and understanding of biomarker testing. To further understand identified gaps, the Alliance recruited a diverse set of patients and caregivers at various stages of the colorectal cancer journey for a focus group to explore understanding around biomarkers, treatment pathways, biomarker testing decisions, and gaps around current testing and re-testing processes. Working with a multidisciplinary expert Advisory Committee, the Alliance utilized findings from the survey and focus group to plan a 2021 Summit focused on identifying solutions for known barriers. Results: Summit participants discussed innovative and evidence-based solutions focused on three audiences: patients, caregivers, and cancer care team members, to close some of the gaps identified previously. Patient solutions focused on developing standard resources that explain biomarker testing and results and updating telehealth infrastructure to allow for clear, transparent notes, patient engagement, and shared decision making. Caregiver solutions focused on clearly defining the role of the caregiver and updating telehealth infrastructure to allow for caregiver support in the journey. Cancer care team solutions focused on creating standard health literacy standards, becoming better advocates for biomarker testing, and creating multidisciplinary discussion opportunities between health professionals. Conclusions: It is critical that we put swift solutions in place with efforts to improve resources, shared language, infrastructure, and advocacy to empower cancer care teams, patients and caregivers alike to receive guideline-concordant biomarker testing, make informed treatment decisions accordingly, and understand the choices and discussions at each step. Acknowledgments: The 2021 Colorectal Cancer Biomarker Think Tank was made possible by the support of our sponsors: Founding Sponsor Pfizer, as well as Amgen, Daiichi-Sankyo, Seagen, Merck, and Mirati Therapeutics. The Alliance is grateful to the Biomarker Think Tank Advisory Committee for their support. Citation Format: Kimberly Lynn Newcomer, Negeen Fathi, Andrea Goodman. A Colorectal Biomarker Think Tank Collaborative: Devising Solutions for Patients, Caregivers, and Cancer Care Teams [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 7.

Abstract 935: NEK1 phosphorylates YAP1 to promote prostate cancer tumorigenesis

Abstract Background: Prostate cancer (PCa) is the second leading cause of cancer death in men of western part of the world. The disease progression has been defined by substages (adenocarcinoma to castration resistant PCa to neuroendocrine PCa) both from mouse models and patients from clinical studies. The mechanism of the disease advancement and hence treatment modalities is still under investigation. Hippo pathway, the evolutionarily conserved developmental pathway, known to regulate organ size, proliferation, apoptosis, migration, stemness etc., is also implicated in PCa tumorigenesis. Transcriptional co-activator YAP1 which acts downstream of the canonical hippo kinases is known to interact with plethora of proteins. But how non-canonical hippo kinases can regulate YAP1 in this disease is yet to be unraveled. We find that NIMA-related kinase isoform 1, Nek1, interacts with YAP1 and phosphorylates Tyr-407 of YAP1. The significance of this post-translational modification is the focus of the study. We find that Nek1 phosphorylates YAP1 to stabilize YAP1 and promote tumorigenesis. Material and Methods: Human YAP1 cDNA encoding plasmid mutated at Tyr 407 to Phenylalanine using site-directed mutagenesis. YAP1-Y407F and WT expressed in HEK293A cells. For genetic analysis in mouse model, female TRAMP mice were bred with Nek1 -/+ male mouse (Jackson laboratory). Genotypic analysis confirmed Nek1-/+ TRAMP and Nek1+/+TRAMP which were used for this study. After 16weeks of age the male mice were castrated and sacrificed at 20weeks of age. Prostate tissues collected and histological sections done (paraffin embedded). Immunohistochemical (IHC) analysis was done using vector labs IHC kits, data analyzed and scored by our pathologist. Results: Immunoblots from YAP1-Y407F and WT cells treated with Cycloheximide (50ug/ml) at different time points (0.5-6hrs) show that YAP1-Y407F is less stable than WT with t1/2 of 0.5hrs whereas WT is stable till 2hrs. Very importantly, while intact TRAMP/Nek1+/- mice do develop PCa normally with much enlargement of the prostate at 18-20 weeks, if these mice are castrated, the tumors fail to grow and the prostate retains normal size and general morphology. Our IHC data confirms that firstly, castrated Nek1+/+TRAMP shows clearly cancerous acini whereas the Nek-/+ TRAMP shows mostly stromal fibrosis and hyperplasia (as shown in H&E and IHC). Secondly, when stained for activated Nek1 marker, pNek1 (T141), we find that Nek1 stain intensity is low in Nek1-/+ tissues compared to Nek1+/+. Most importantly, YAP1 level is lower in the same parallel tissue sections of Nek1-/+. From the above analysis, we conclude that Nek1 activity regulates stability of YAP1, and infer that YAP1 function is critical for the timely progression to adenocarcinoma following androgen deprivation therapy. Acknowledgements: Funding Resources: Department of Defense (DoD-PCRP grant W81XWH-17-1-0417) ; FWCC Bridge Award. Citation Format: Ishita Ghosh, Zobair Alam, Md. Imtiaz Khalil, Judy King, Arrigo DeBenedetti. NEK1 phosphorylates YAP1 to promote prostate cancer tumorigenesis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 935.

Abstract 110: Elevation of pro-apoptotic protein, PUMA, contributes to the growth suppression of lung cancer by platycodin D

Abstract Lung cancer is the most devastating disease and leading cause of cancer death in men and women. Platycodin D is one of the major bioactive components of the Platycodon grandiflorum, a herb that is frequently used for the treatment of lung diseases in Chinese medicine. Platycodin D is a triterpenoid monomer with activities of antioxidant, anti-obesity, and anti-inflammatory. Studies have also shown that platycodin D has an anti-tumor effect on various types of cancer. However, the mechanism by which platycodin D suppresses tumorigenesis remains elusive and some experimental results are controversial. In this study, we aim to understand the effect of platycodin D on the growth of non-small lung cancer cells (NSCLC) and the underlying mechanism. We found that NSCLC cells (H1299, H2030, and A549 cells) treated with platycodin D significantly reduced the cell viability, decreased the number of colonies, impaired the mitochondrial function, and induced apoptosis. To understand the mechanism, the protein levels of the Bcl-2 protein family were examined and p53 upregulated modulator of apoptosis (PUMA) was found elevated by platycodin D treatment. The induction of PUMA expression by platycodin D treatment was through activation of the c-Jun N-terminal kinase (JNK) and AP-1 dependent transcription since JNK inhibitor or over-expression of dominant negative c-Jun abolished the elevated PUMA expression. Moreover, knockdown of JNK1, but not JNK2, significantly decreased the level of platycodin D-induced PUMA and cleaved caspase 3, indicating the essential role of JNK1 in platycodin D-induced apoptosis. Furthermore, platycodin D efficiently suppressed the tumor growth in the H1299 xenograft. Taken together, activation of JNK1 by platycodin D is essential for induction of apoptosis in suppression of growth of NSCLC, providing a new mechanism of how platylcodin D suppresses NSCLC. Citation Format: Qing Wang, Hsin-Sheng Yang. Elevation of pro-apoptotic protein, PUMA, contributes to the growth suppression of lung cancer by platycodin D [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 110.

Abstract 3526: Host genetic susceptibility to gut microbiota-driven colorectal carcinogenesis

Abstract Introduction: Colorectal cancer (CRC) is the 1st and 2nd leading cause of cancer death in men and women in Puerto Rico and the U.S., respectively. A dynamic balance between the host immune system and the gut bacterial communities is essential to protect colonic tissues against chronic inflammation, which may lead to CRC. The main goal of this study was to investigate if SNPs in the promoter regions of the IL-1β, IL-6 and IL-10, key cytokines that regulate gut inflammation, increase the risk for colorectal adenomas by enriching a subset of the toxin-producing gut microbiota (gene-environment interaction). Methods: Using a case-control study design, associations between having pro-inflammatory SNPs and/or bacterial toxins in colonic mucosa or stool were assessed using odds ratios. TaqMan® SNP Genotyping Assays (ThermoFisher Scientific) for IL- 1β (rs1143627), IL-6 (rs1800795), and IL-10 (rs1800871) were performed according to the manufacturer’s recommendations. The presence of bacterial toxin genes (pks, TcPC, GelE, cnf-1, CDT, murB, and usp) in stool were determined using the QuantiTect SYBR Green PCR kit (QIAGEN). Results: Our preliminary analyses showed that individuals with the IL-1β pro-inflammatory genotype were 1.5-times more likely to have colorectal adenomas (n=232; p=0.1). Detection of usp or pks in stool (n=147) was positively associated with having adenomas (OR=2.95; CI 95%= 0.92-9.45 and OR=2.91; CI 95%=0.58-14.50, respectively). Conclusion: An evaluation of the association between having pro-inflammatory genotypes, the presence of bacterial toxin genes in stool, and colorectal adenomas using a larger sample size is warranted and currently underway. The integration of modifiable (e.g. gut bacterial toxins) and non-modifiable (e.g. host genetics) risk factors in a stratified model for CRC risk stratification and/or prevention may enhance current screening approaches. Citation Format: Ibis R. Vera-Urbina, Estefania Ayala, Ediel Rodriguez, Hilmaris Centeno-Girona, Leslie Casiano, Belisa Suarez, Marcia Cruz-Correa, Maria Gonzalez-Pons. Host genetic susceptibility to gut microbiota-driven colorectal carcinogenesis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3526.

Liver Cirrhosis Increases the Risk of Developing Advanced Colon Polyps.

To analyze our experience with adenoma detection rates in patients with liver cirrhosis in a community setting. Colorectal cancer (CRC) is the third most common cancer and leading cause of cancer death in men and women in the USA. The majority of CRCs arise from premalignant polyps (adenomas), which are typically detected and removed during colonoscopy. Data are limited on the risk of CRC in patients with various chronic liver diseases and the association between CRC and demographics, liver disease etiology and colonoscopy findings. A total of 351 colonoscopies were performed (2006 to 2019) in patients with liver cirrhosis. Mean age was 62.3 ± 9.4years, there were 158 females and 193 males. Adenomas were found in 159 procedures (49.07%) and were more likely found in the right colon (76.73%) vs the left colon (18.87%). Left-sided adenoma occurrence was significantly lower in women (61% lower than men, p = 0.05). Neither indication for the procedure (p = 0.08) nor advancing age (p = 0.94) affected adenoma detection rates. No significant differences were observed in the findings of adenomas between different chronic liver diseases. Adenoma detection rates in patients with cirrhosis (49%) undergoing elective colonoscopy were higher than rates reported in the literature for LT candidates (22-42%) undergoing standardized screenings. Colonoscopy screenings should be expanded to all patients with cirrhosis, regardless of etiology.

PTEN-PI3K pathway alterations in advanced prostate cancer and clinical implications.

Despite significant advances in molecular characterization and therapeutic targeting of advanced prostate cancer, it remains the second most common cause of cancer death in men in the United States. The PI3K (Phosphatidylinositol 3-kinase)/AKT (AKT serine/threonine kinase)/mTOR (mammalian target of rapamycin) signaling pathway is commonly altered in prostate cancer, most frequently through loss of the PTEN (Phosphatase and Tensin Homolog) tumor suppressor, and is critical for cancer cell proliferation, migration, and survival. This study summarizes signaling through the PTEN/PI3K pathway, alterations in pathway components commonly seen in advanced prostate cancer, and results of clinical trials of pathway inhibitors reported to date with a focus on more recently reported studies. It also reviews rationale for combination approaches currently under study, including with taxanes, immune checkpoint inhibitors and poly (ADP-ribose) polymerase inhibitors, and discusses future directions in biomarker testing and therapeutic targeting of this pathway. Clinical trials studying pharmacologic inhibitors of PI3K, AKT or mTOR kinases have demonstrated modest activity of specific agents, with several trials of pathway inhibitors currently in progress. A key challenge is the importance of PI3K/AKT/mTOR signaling in noncancerous tissues, leading to predictable but often severe toxicities at therapeutic doses. Further advances in selective pharmacologic inhibition of the PI3K/AKT/mTOR pathway in tumors, development of rational combinations, and appropriate biomarker selection to identify the appropriate tumor- and patient-specific vulnerabilities will be required to optimize clinical benefit from therapeutic targeting of this pathway.

A colorectal biomarker think tank collaborative: Devising solutions for patients, caregivers, and cancer care teams.

e15507 Background: Colorectal cancer is the third-most commonly diagnosed cancer and the second-leading cause of cancer death in men and women combined in the United States. With more than a dozen known mutations in colorectal cancer, and growing knowledge about different efficacy of drug options dependent on biomarker status, biomarker testing and results can aid in more effective and lifesaving treatment planning specifically for the unique characteristics of each individual’s tumor. However, biomarker testing in colorectal cancer remains low, and the Colorectal Cancer Alliance aims to increase knowledge and awareness of testing among patients and their care teams. Methods: In 2019, the Alliance distributed an online survey to assess patient, survivor, and caregiver knowledge and understanding of biomarker testing. The results identified patient confusion, suboptimal biomarker testing rates, and critical aspects of patients' medical treatment plan. To further understand identified gaps, the Alliance recruited a diverse set of patients and caregivers at various stages of colorectal cancer for a focus group in 2021 to explore understanding around biomarkers, treatment pathways, biomarker testing decisions, and gaps around current testing and re-testing processes. Working with an expert Advisory Committee, the Alliance utilized findings from the survey and focus group to plan a 2021 Summit focused on identifying solutions for known barriers. Results: Summit participants discussed innovative and evidence-based solutions focused on three audiences: patients, caregivers, and cancer care team members, to close some of the gaps identified previously. Patient solutions focused on cancer field-wide collaborations to create standard language and health literacy standards for biomarkers and testing that allow for clear, transparent notes, patient engagement, and shared decision making. Caregiver solutions focused on elevating the caregiver role as an advocate through updated telehealth infrastructure that allows for caregiver support in the journey. Cancer care team solutions focused on utilizing continuing medical education (CME) courses to create standard health literacy standards, become better advocates for biomarker testing, and create multidisciplinary discussion opportunities between health professionals. Conclusions: Patients and caregivers are overwhelmed by the complexity and variety of treatment options. It is critical that we put swift, collaborative solutions in place with efforts to improve resources, shared language, infrastructure, and advocacy to empower cancer care teams, patients and caregivers alike. We aim to increase knowledge of and access to guideline-concordant biomarker testing, so that patients, caregivers, and cancer care teams can make informed treatment decisions accordingly, and understand the choices and discussions at each step.

The need for a personalized, comprehensive resource within the colorectal cancer community.

e24139 Background: Colorectal cancer is the third-most commonly diagnosed cancer and the second-leading cause of cancer death in men and women combined in the United States. In efforts to manage the disease, patients and caregivers turn to a variety of tools and resources for financial assistance, information dissemination, emotional and peer support, and treatment planning, among other critical issues and needs they face. The Colorectal Cancer Alliance (the Alliance) is committed to providing patients and caregivers with a resource solution that encompasses all potential areas of need. Methods: A survey aimed at understanding needs, barriers, and quality improvement opportunity was disseminated via the Alliance's Blue Hope Nation community for two weeks and by email. One hundred sixty-seven colorectal cancer patients and forty caregivers of colorectal cancer patients completed the survey. Results: Patients and caregiver respondents alike report reliance on external tools and resources to manage disease and support information. Of the support methods, patient respondents reported using social media (46.11%); notebooks, journals, and planners (45.41%); online articles (44.91%); the Blue Hope Nation Facebook group (41.32%); cancer discussion boards (35.33%); and spiritual or religious advice (29.94%). Caregiver respondents reported relying on friends and family (57.5%); the Blue Hope Nation Facebook group (47.5%); healthcare websites (47.5%); the Alliance website (42.5%); and spiritual or religious advisors (37.5%). To minimize diagnosis-related stressors, patients reported they look for financial assistance, local peer support and groups, and mental health help. To provide more efficient care and limit stress, the community suggested the need for financial help, communication and support from other patients and caregivers, and informational resources. Conclusions: These survey results are consistent with other published learnings about patient and caregiver reliance on support tools and highlights the myriad resources that patients and caregivers currently use for managing colorectal cancer. The saturation of the market has compelled the Colorectal Cancer Alliance to create a one-stop-shop, personalized resource with tools to organize and effortlessly share customized information treatment plans, and other support mechanisms. Such patient and caregiver-directed resources may enable a better care experience and potentially lead to better physical and mental health outcomes for patients and their caregivers.