Opportunities For Cancer Management Research Articles

Histone Deacetylase Inhibitors, Intrinsic and Extrinsic Apoptotic Pathways, and Epigenetic Alterations of Histone Deacetylases (HDACs) in Hepatocellular Carcinoma.

Epigenetics is the study of heritable modifications in gene expression and reversible forms of gene regulation. Recent in-vitro works have indicated that epigenetics plays a significant role in many types of human cancers e.g. hepatocellular carcinoma (HCC). Diverse cellular functions are regulated by histone acetylation and deacetylation. Histone deacetylases (HDACs) and histone acetylases (HATs) are enzymes involved in chromatin remodeling histone deacetylation and acetylation respectively. Aberrant protein acetylation, particularly histone deacetylation, has been reported in a broad range of human cancer types. Epigenetic modification by inhibiting HDAC activity is an emerging approach in cancer treatment. HDACIs play their apoptotic roles through multiple mechanisms such as extrinsic/cytoplasmic and intrinsic/mitochondrial molecular mechanisms. Here, we summarize the major classes of HDACs and epigenetic compounds, HDACIs, and also their molecular mechanisms in HCC including intrinsic and extrinsic apoptotic pathways. An online search of different sources including PubMed, ISI, and Scopus was achieved to find suitable data on mechanisms and pathways of HDACs and HDACIs in HCC. The result demonstrated that the dysregulation of HDACs because of histone deacetylation induces HCC. The histone deacetylation can be reversed by HDACIs resulting in apoptosis induction. In conclusion, because histone deacetylation is a potentially reversible change, epigenetic histone modification represents new opportunities for cancer management by reactivation of gene silencing. The inhibition of HDACs by GDACIs can effectively induce apoptosis and suppress cancer cell proliferation. These compounds can engage both intrinsic and extrinsic apoptotic pathways.

Outpatient acupuncture effects on patient self-reported symptoms in oncology care: A retrospective analysis of real-world data.

135 Background: Increased access to complementary therapies such as acupuncture at academic medical centers has created new opportunities for management of cancer and cancer treatment related symptoms. Methods: Patients presenting for acupuncture treatment during calendar year 2016 at an outpatient integrative medicine clinic in a comprehensive cancer center were asked to complete a modified Edmonton Symptom Assessment Scale (ESAS; 16 symptoms, score 0-10, 10 worst possible) before and after each visit. ESAS subscales analyzed included global (GDS; score 0-90), physical (PHS, 0-60), and psychological distress (PSS, 0-20). ESAS symptom score change pre/post treatment and from baseline visit to first follow up were evaluated by paired t-test. Results: Of 375 participants [mean age 55.6, 68.3% female, 73.9% white, most common cancer diagnosis of breast (32.8%) and thoracic/head&neck (25.9%)], 73.3% had at least one follow-up treatment [mean 4.6 (SD 5.1) treatments]. Highest/worst symptoms at baseline were poor sleep (3.92), fatigue (3.43), well-being (3.31), and pain (3.29). Statistically significant reduction/improvement (pre/post) was observed for all ESAS symptoms and subscales for the initial treatment (p <0.001). Hot flashes had the highest mean reduction (-1.93), followed by fatigue (-1.72), numbness/tingling (-1.70), and nausea (-1.67). Clinically significant reductions were also observed for ESAS subscales of GDS (-12.2), PHS (-8.5), and PSS (-2.6). For symptom change from initial treatment to first follow-up (pre/pre), statistically and clinically significant improvement was observed for spiritual pain (-1.10; p<0.001) and ESAS subscale of GDS (-6.09; p=0.048). Clinical response rates (reduction ≥1) on follow-up were highest for symptoms of spiritual pain (58.9%), dry mouth (57.8%) and nausea (57.3%). Conclusions: Outpatient acupuncture was associated with immediate and longitudinal significant improvement across a range of symptoms commonly experienced by individuals during cancer care. Further research is needed to better understand frequency of treatments needed in clinical practice to help maintain benefit.

Outpatient acupuncture effects on patient self-reported symptoms in oncology care: a retrospective analysis.

Background: Increased access to complementary therapies such as acupuncture at academic medical centers has created new opportunities for management of cancer and cancer treatment related symptoms.Methods: Patients presenting for acupuncture treatment during calendar year 2016 at an outpatient integrative medicine clinic in a comprehensive cancer center were asked to complete a modified Edmonton Symptom Assessment Scale (ESAS; 16 symptoms, score 0-10, 10 worst possible) before and after each visit. ESAS subscales analyzed included global (GDS; score 0-90), physical (PHS, 0-60) and psychological distress (PSS, 0-20). ESAS symptom score change pre/post acupuncture treatment & from baseline visit to first follow up were evaluated by paired t-test.Results: Of 375 participants [mean age 55.6, 68.3% female, 73.9% white, most common cancer diagnosis of breast (32.8%) and thoracic/head & neck (25.9%)], 73.3% had at least one follow up acupuncture treatment [mean 4.6 (SD 5.1) treatments]. Highest/worst symptoms at baseline were poor sleep (3.92), fatigue (3.43), well-being (3.31), and pain (3.29). Statistically significant reduction/improvement (pre/post) was observed for all ESAS symptoms and subscales for the initial acupuncture treatment (p <0.001). Hot flashes had the highest mean reduction (-1.93), followed by fatigue (-1.72), numbness/tingling (-1.70), and nausea (-1.67). Clinically significant reductions were also observed for ESAS subscales of GDS (-12.2), PHS (-8.5), and PSS (-2.6). For symptom change from initial acupuncture treatment to first follow up (pre/pre), statistically and clinically significant improvement was observed for spiritual pain (-1.10; p<0.001) and ESAS subscale of GDS (-6.09; p=0.048). Clinical response rates (reduction ≥1) on follow up were highest for symptoms of spiritual pain (58.9%), dry mouth (57.8%) and nausea (57.3%).Conclusions: Outpatient acupuncture was associated with immediate & longitudinal significant improvement across a range of symptoms commonly experienced by individuals during cancer care. Further research is needed to better understand frequency of treatments needed in clinical practice to help maintain benefit.

Abstract 35: Diacylglycerol kinase zeta-mediated regulation of mTOR and SREBP-1 offers new opportunities for cancer management

Abstract Diacylglycerol (DAG) and phosphatidic acid (PA) are two lipids that lie at the core of several metabolic and signaling pathways, which allows integrated control of cell growth and nutrient sensing with cell metabolism. Diacylglycerol kinases (DGK) are a family of enzymes that balance the levels of both lipids. Some DGK isoforms, mainly DGKα, have been recently suggested as potential targets for cancer treatment (Dominguez et al, 2013; Torres-Ayuso et al, 2014). Previous observations from us indicate that the DGKζ isoform contributes the most to DGK activity in cancer cells, and DGKζ-derived PA is required for mTOR activation, a master regulator of cell growth and metabolism (Avila-Flores et al, 2005). To address the potential of DGKζ as new therapeutic target for cancer treatment, we used several breast and colon cancer cell lines, and analyzed the effect of its pharmacological inhibition or siRNA-mediated knock down in the proliferation, survival and metabolism of these cells. We found that DGKζ protein levels where higher in malignant cells compared to their non-transformed counterparts, and its depletion abrogated cancer cell growth in colony assays. DGKζ was prominent over other PA sources to activate mTOR, and its activity was induced by rapamycin. We also investigated whether DGKζ-derived PA functions were coordinated with DAG metabolism and signaling. We observed that DGKζ-dependent DAG consumption was crucial for cell homeostasis via control of the SREBP-1 transcription factor, which was negatively regulated by DAG. Our data provide new evidence of the crosstalk between mTOR and lipid metabolism, and suggest that DGKζ represents an effective target for cancer control. References Avila-Flores A, Santos T, Rincon E, Merida I (2005) Modulation of the mammalian target of rapamycin pathway by diacylglycerol kinase-produced phosphatidic acid. The Journal of biological chemistry 280: 10091-10099 Dominguez CL, Floyd DH, Xiao A, Mullins GR, Kefas BA, Xin W, Yacur MN, Abounader R, Lee JK, Wilson GM, Harris TE, Purow BW (2013) Diacylglycerol kinase alpha is a critical signaling node and novel therapeutic target in glioblastoma and other cancers. Cancer discovery 3: 782-797 Torres-Ayuso P, Daza-Martin M, Martin-Perez J, Avila-Flores A, Merida I (2014) Diacylglycerol kinase alpha promotes 3D cancer cell growth and limits drug sensitivity through functional interaction with Src. Oncotarget 5: 9710-9726 Citation Format: PEDRO Torres-Ayuso, David Jones, Maria Tello-Lafoz, Antonia Avila-Flores, Isabel Merida. Diacylglycerol kinase zeta-mediated regulation of mTOR and SREBP-1 offers new opportunities for cancer management. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 35. doi:10.1158/1538-7445.AM2015-35

Opportunities for better management of cancer in patients receiving chemotherapy at Aurora Health Care (AHC), a large integrated health system in eastern Wisconsin.

110 Background: Cancer patients, especially those on chemotherapy, have complex medical histories. They experience a variety of medical problems from their cancer and treatments. This quality improvement study is designed to collect information about chemotherapy related emergency department (ED) visits to estimate ED utilization rates, recognize patterns and evaluate other confounders. The goal is to assess and reduce ED use at AHC through improved care management. Methods: The one-year data analysis includes any patient who received chemotherapy in an outpatient care setting and had a visit to the ED within 60 days of treatment. Chemotherapy was defined by designated CPT codes combined with a primary cancer diagnosis. Every ED visit was matched to all available chemotherapy visits for each patient, retaining the chemotherapy visit nearest in chronology prior to the ED visit. Data Exclusions: (a) Patients who received chemotherapy outside AHC, and then accessed an AHC ED; (b) Patients who received inpatient chemotherapy. Results: There were 28,738 chemotherapy encounters for 4,264 unique patients system-wide. AHC EDs saw 1,669 visits for 1,048 unique patients within 60 days of chemotherapy (24.6%). The top three cancer diagnoses were 21% thoracic; 21% GI; and 16% lymph/hematopoietic. Of the 1,669 ED visits, 35% occurred within seven days and 77% within 30 days of treatment. Almost half (45.6%) of the ED visits occurred during normal office hours. No significant variation was noted by day of week. An initial focus was on the tertiary center which represented 318 (20%) of the 1,669 ED visits. The most common diagnoses for an ED visit were pain (17%) and deconditioning (17%), followed by infection (11%) and respiratory symptoms (11%). Conclusions: This study documents the ED utilization by AHC chemotherapy patients. Unexpectedly, ED use occurred frequently during normal office hours. Most visits were represented by a limited number of cancer diagnoses and presenting complaints. Intervention is planned to reduce ED use after chemotherapy at AHC through improved patient education and by shifting these visits to less expensive venues when possible.

Contribution of uric acid to cancer risk, recurrence, and mortality

Two risk factors for the development and progression of cancers that are amenable to life style modification are chronic inflammation and the metabolic syndrome. This review proposes two new targets that may mechanistically integrate inflammation and metabolic syndrome, have been largely ignored, and are known to be druggable. Recent evidence has demonstrated that elevated serum uric acid (hyperuricemia) is associated with excess cancer risk, recurrence, and mortality. Although uric acid (UA) can function as a systemic antioxidant, its pro-inflammatory properties have been postulated to play an important role in the pathogenesis of cancer. Furthermore, obesity, Type 2 Diabetes Mellitus (T2DM), and the metabolic syndrome (MetS) are also associated with excess cancer, chronic inflammation, and with hyperuricemia, suggesting that UA may represent an important link between these disorders and the development of cancer. While pharmacological modulation of hyperuricemia could in principal augment anti-cancer therapeutic strategies, some cancer cells express low intracellular levels of the enzyme Xanthine Oxidoreductase (XOR) that are associated with increased cancer aggressiveness and poor clinical outcome. Thus, systemic pharmacological inhibition of XOR may worsen clinical outcome, and specific strategies that target serum uric acid (SUA) without inhibiting tumor cell XOR may create new therapeutic opportunities for cancer associated with hyperuricemia. This review will summarize the evidence that elevated SUA may be a true risk factor for cancer incidence and mortality, and mechanisms by which UA may contribute to cancer pathogenesis will be discussed in the hope that these will identify new opportunities for cancer management.

Abstract 4594: Grape seed extract induces apoptosis in human colorectal carcinoma through modulation of death receptors and anti-apoptotic molecules

Abstract Colorectal Cancer (CRC) is the second leading cause of cancer related deaths in the US. Diets rich in fruits and vegetables are shown to decrease CRC incidence by 40%, in part due to antioxidant and free radical properties of the polyphenolics present therein; grape seed extract (GSE) is one of the richest sources of these antioxidants. Oncogenic mutations that suppress apoptosis can lead to tumor initiation, progression, and metastasis; a major cause of conventional treatment resistance is due to apoptotic pathway defects. Accordingly, the strategies that target the mechanisms of apoptosis resistance in cancer cells provide the potential opportunities for cancer management. Herein we investigated the apoptotic effects of GSE and defined associated mechanisms in three human CRC cell lines, namely SW480, SW620 and HCT116, representing II-IV stages of CRC. Normal colon epithelial cells namely NCM460 was also included to establish GSE specificity, if any, towards CRC cells. A comparison of GSE activity in three CRC cell lines showed that almost three times higher GSE levels are needed for comparable cell death effect in SW480 versus SW620/HCT116 cells; cell treatments were accordingly adjusted for remainder studies. GSE treatment of SW480 cells at 25-100μg/mL resulted in a maximum of 55% apoptotic death at 48h; however, even 10-30μg/mL GSE treatments produced 53-57% apoptotic cell death in SW620 and HCT116 cell lines. At the molecular level, GSE induced DR4/5 up regulation, caspase-9, -3, -8, and PARP cleavage in all three cell lines indicating the involvement of both extrinsic and intrinsic apoptotic pathways in its efficacy. Furthermore, GSE treatment caused down regulation of anti-apoptotic proteins Bcl-2 and XIAP in SW480 cells only, but increased the levels of pro-apoptotic proteins such as Mcl-1s in all three cell lines. Importantly, GSE also increased the levels of p53 and its associated regulators namely p21, PUMA and Bak, suggesting their possible role in GSE-caused apoptotic death in HCT116 cell line. GSE treatment (25-100μg/mL) of NCM460 cells did not result in significant death compared to what was observed in three different human CRC cell lines, clearly showing its activity selectively in cancer cells. In conclusion, our findings further support the notion that GSE could be an effective chemopreventive and chemotherapeutic agent for colorectal. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4594. doi:10.1158/1538-7445.AM2011-4594

Regulation of Mitosis via Mitotic Kinases: New Opportunities for Cancer Management

Mitosis, a critical and highly orchestrated event in the cell cycle, decides how cells divide and transmit genetic information from one cell generation to the next. Errors in the choreography of these events may lead to uncontrolled proliferation, aneuploidy, and genetic instability culminating in cancer development. Considering the central role of phosphorylation in mitotic checkpoints, spindle function, and chromosome segregation, it is not surprising that several mitotic kinases have been implicated in tumorigenesis. These kinases play pivotal roles throughout cellular division. From DNA damage and spindle assembly checkpoints before entering mitosis, to kinetochore and centrosome maturation and separation, to regulating the timing of entrance and exit of mitosis, mitotic kinases are essential for cellular integrity. Therefore, targeting the mitotic kinases that control the fidelity of chromosome transmission seems to be a promising avenue in the management of cancer. This review provides an insight into the mechanism of mitotic signaling, especially the role of critical mitotic kinases. We have also discussed the possibilities of the use of mitotic kinases in crafting novel strategies in cancer management. [Mol Cancer Ther 2007;6(7):1920–31]

Regulation of mitosis via mitotic kinases: new opportunities for cancer management

Mitosis, a critical and highly orchestrated event in the cell cycle, decides how cells divide and transmit genetic information from one cell generation to the next. Errors in the choreography of these events may lead to uncontrolled proliferation, aneuploidy, and genetic instability culminating in cancer development. Considering the central role of phosphorylation in mitotic checkpoints, spindle function, and chromosome segregation, it is not surprising that several mitotic kinases have been implicated in tumorigenesis. These kinases play pivotal roles throughout cellular division. From DNA damage and spindle assembly checkpoints before entering mitosis, to kinetochore and centrosome maturation and separation, to regulating the timing of entrance and exit of mitosis, mitotic kinases are essential for cellular integrity. Therefore, targeting the mitotic kinases that control the fidelity of chromosome transmission seems to be a promising avenue in the management of cancer. This review provides an insight into the mechanism of mitotic signaling, especially the role of critical mitotic kinases. We have also discussed the possibilities of the use of mitotic kinases in crafting novel strategies in cancer management.