Cancer Treatment Pathway Research Articles

Targeting the Ubiquitin-Proteasome Pathway: An Emerging Concept in Cancer Therapy

Selective degradation of proteins by the ubiquitin-proteasome pathway is a critical determinant for maintaining cellular homeostasis. Most intracellular proteins are degraded by the proteasome, a multicatalytic enzyme complex containing a 20S catalytic core and two 19S regulatory complexes. Many proteasome target proteins are involved in the regulation of important processes of carcinogenesis and cancer cell survival, such as cell cycle progression, cell proliferation, differentiation and apoptosis. Indeed, the ubiquitin-proteasome-dependent degradation pathway plays an essential role in both the up-regulation of cell proliferation and down-regulation of cell death in human cancer cells. Both in vitro and in vivo experimental and clinical results have demonstrated the potential use of proteasome inhibitors as novel anticancer drugs. Proteasome inhibition in cancer cells leads to accumulation of pro-apoptotic target proteins followed by induction of cell death. The clinical efficacy of the proteasome inhibitor bortezomib toward multiple myeloma and other hematologic malignancies provides the "proof of concept" that targeting the proteasome is a promising strategy for cancer treatment. Several other proteasome inhibitors have also been identified from natural resources, such as marine microbial metabolites, green tea polyphenols, flavonoids, and medicinal compounds. Additionally, the use of metal complexes as proteasome inhibitors has also been investigated as a potential anticancer strategy. The clinical significance of targeting the tumor survival-associated proteasome pathway for cancer treatment, intervention and prevention will be discussed.

Transatlantic Consensus Group on active surveillance and focal therapy for prostate cancer

What's known on the subject? and What does the study add? Active surveillance for prostate cancer is gaining increasing acceptance for low risk prostate cancer. Focal therapy is an emerging tissue preservation strategy that aims for treat only areas of cancer. Early phase trials have shown that side-effects can be significantly reduced using focal therapy. There is significant uncertainty in both active surveillance and focal therapy. This consensus group paper provides a road-map for clinical practice and research for both tissue-preserving strategies in the areas of patient population, tools for risk stratification and cancer localisation, treatment interventions as well as comparators and outcome measures in future comparative trials. To reach consensus on key issues for clinical practice and future research in active surveillance and focal therapy in managing localized prostate cancer. A group of expert urologists, oncologists, radiologists, pathologists and computer scientists from North America and Europe met to discuss issues in patient population, interventions, comparators and outcome measures to use in both tissue-preserving strategies of active surveillance and focal therapy. Break-out sessions were formed to provide agreement or highlight areas of disagreement on individual topics which were then collated by a writing group into statements that formed the basis of this report and agreed upon by the whole Transatlantic Consensus Group. The Transatlantic group propose that emerging diagnostic tools such as precision imaging and transperineal prostate mapping biopsy can improve prostate cancer care. These tools should be integrated into prostate cancer management and research so that better risk stratification and more effective treatment allocation can be applied. The group envisaged a process of care in which active surveillance, focal therapy, and radical treatments lie on a continuum of complementary therapies for men with a range of disease grades and burdens, rather than being applied in the mutually exclusive and competitive way they are now. The changing landscape of prostate cancer epidemiology requires the medical community to re-evaluate the entire prostate cancer diagnostic and treatment pathway in order to minimize harms resulting from over-diagnosis and over-treatment. Precise risk stratification at every point in this pathway is required alongside paradigm shifts in our thinking about what constitutes cancer in the prostate.

MiR-148a inhibits angiogenesis by targeting ERBB3

MicroRNAs (miRNAs) play an important role in carcinogenesis in various solid cancers including breast cancer. Down-regulation of microRNA-148a ( miR-148a) has been reported in certain cancer types. However, the biological role of miR-148a and its related targets in breast cancer are unknown yet. In this study, we showed that the level of miR-148a was lower in MCF7 cells than that in MCF10A cells. V-erb-b2 erythroblastic leukemia viral oncogene homolog 3 ( ERBB3) is a direct target of miR-148a in human breast cancer cells through direct binding of miR-148a to ERBB3 3′-UTR region. Overexpression of miR-148a in MCF7 cells inhibited ERBB3 expression, blocked the downstream pathway activation including activation of AKT, ERK1/2, and p70S6K1, and decreased HIF-1α expression. Furthermore, forced expression of miR-148a attenuated tumor angiogenesis in vivo. Our results identify ERBB3 as a direct target of miR-148a, and provide direct evidence that miR-148a inhibits tumor angiogenesis through ERBB3 and its downstream signaling molecules. This information would be helpful for targeting the miR-148a/ERBB3 pathway for breast cancer prevention and treatment in the future.

Abstract 591: Expanding the therapeutic window through pharmacological activation of the RB pathway in breast cancer treatment

Abstract Triple negative breast cancer (TNBC) is a highly aggressive disease that is most often treated with cytotoxic chemotherapies, such as anthracyclines and platinum compounds. While effective for certain tumors, these therapies are known to cause severe toxicities in numerous tissues. Thus, targeting pathways to both exploit therapy-sensitive tumors and ameliorate tissue toxicity is of utmost significance. Loss of the retinoblastoma tumor suppressor (RB) protein is a frequent event in TNBC, and is expected to alter therapeutic sensitivity by perturbing cell cycle checkpoints and yielding a predilection towards cell death. Conversely, it is possible that the same principles that drive sensitivity to cytotoxic agents in an RB-deficient setting could be used to prevent toxicities in an RB-proficient setting (i.e. normal tissues). Thus, modulation of the RB pathway could be critical for expanding the therapeutic window in the treatment of breast cancer. To address this hypothesis, combination studies of pharmacological activation of the RB pathway and cytotoxic chemotherapies commonly used to treat TNBC were performed in vitro and in vivo. Results indicate that activation of the RB pathway can modulate the efficacy of cytotoxic compounds in the treatment of TNBC. The mechanisms behind these observations were attributed directly to RB-mediated regulation of DNA damage and repair signaling pathways, as well as apoptosis. RB-deficiency resulted in bypass of these mechanisms and thus enhanced sensitivity to cytotoxic therapies. These results were supported by in silico data demonstrating that RB-deficient TNBC is associated with better clinical outcome in response to chemotherapy. Importantly, functional studies indicated that RB pathway activation can provide protection against the toxicity of frequently used chemotherapeutic compounds in normal tissue. Combined, these studies suggest that RB pathway status could be utilized in the clinic to direct combination treatments that would exploit the sensitivity of RB-deficient tumors to cytotoxic chemotherapies while simultaneously providing protection for normal tissues. 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 591. doi:10.1158/1538-7445.AM2011-591

Abstract 3406: Understanding molecular pathway differences between ovarian cancer stem cells (OCSC) and non-ovarian cancer stem cells (non-OCSC) leads to the Hedgehog pathway as a common thread

Abstract Background: We hypothesize that numerous molecular differences exist between ovarian cancer stem cells (OCSC) and non-ovarian cancer stem cells (non-OCSC). Identifying these differences and describing their cellular interactions could be utilized as sites of targeted therapies for more effective treatment strategies. Methods: Fluorescence Activated Cell Sorting (FACS) was utilized to sort 2 papillary serous ovarian cancer cell lines (OV90 & SKOV3) into 2 distinct populations: OCSC (CD44+/CD24-) and non-OCSC (all other cells). RNA was isolated from each sorted cell subtype, converted to cDNA, and analyzed via PCR array designed to evaluate numerous molecular pathways described in cancer. This array profiles the expression of 84 genes representative of 6 biological functional pathways involved in tumorigenesis. Molecular pathway mapping identified a common molecular pathway, the Hedgehog (Hh) pathway. Expression of Hh pathway proteins (SMOH, PTCH, GLI1) was determined by Western blot. Localization of intranuclear GLI1, which signifies activated Hh pathway, was detected via immunofluorescent staining of GLI1. Cancer cell growth was evaluated after treatment with Hh agonists (SHH and IHH) as well as treatment with an Hh inhibitor (cyclopamine) with and without standard chemotherapy. Results: Genes with ≥ 2-fold upregulation in OCSC compared to non-OCSC where considered significant. Genes grouped by function are as follows: Apoptosis: BCL2 (+2.5), CFLAR (+2.6), and MDM2 (+3.4); Angiogenesis: PIK3R1 (+3.4), VEGFA (+5.1), FGFR2 (+5.1), ANGPT2 (+6.0), and THBS1 (+6.1); Invasion: MMP1 (+2.3), SNCG (+2.7), PLAU (+3.0), and PLAUR (+5.8); and Adhesion: ITGA2 (+9.4). Molecular pathway mapping from these upregulated genes identified the Hh pathway as a common pathway. OV90 and SKOV3 demonstrated increased intranuclear GLI1 expression indicating an activated Hh pathway. Immunofluorescent-staining of GLI1 confirmed these innate findings, however near complete exclusion of intranuclear GLI1 was seen with anti-SMOH treatment with cyclopamine. Both Hh agonists demonstrated significant increases in cancer growth of at least 42-fold for SHH-treated cells and 46-fold for IHH-treated cells (p< 0.001). Inhibition of the Hh pathway with cyclopamine demonstrated a 5-fold decrease in cancer cell growth when used in combination with paclitaxel and carboplatin (p < 0.001). Conclusions: Based on the numerous molecular differences between OCSC and non-OCSC, the Hedgehog pathway appears to be important in OCSC regulation. As such, the inhibition of Hh pathway in combination with standard chemotherapy for ovarian cancer warrants further evaluation of the potential targeting of this pathway in ovarian cancer treatment. 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 3406. doi:10.1158/1538-7445.AM2011-3406

Activity of a novel dual PI3-kinase/mTOR inhibitor NVP-BEZ235 to enhance antitumor activities of gemcitabine and EMAP II in pancreatic cancer.

255 Background: Gemcitabine (Gem, G) has limited benefits as single agent or in combination for pancreatic ductal adenocarcinomas (PDACs). The phosphatidylinositol-3-kinase (PI3K)/AKT and mammalian target of rapamycin (mTOR) signaling pathways are frequently dysregulated in diverse human cancers including PDAC. NVP-BEZ235 (BEZ, B) is a novel dual PI3K/mTOR inhibitor that has been shown to have antitumor activity in multiple tumor types. Endothelial monocyte activating polypeptide II (EMAP, E) is an antiendothelial and antiangiogenic agent that enhances Gem and docetaxel activity in PDAC. We tested the combination benefits of BEZ and Gem in addition to EMAP in experimental PDAC. Methods: In vitro cell proliferation and protein expression were analyzed by WST-1 assay and Western blotting. In vivo animal survival experiments were performed in NOD-SCID PDAC xenografts. Results: Cultured cells of PDAC (AsPC-1), endothelial (HUVECs), and fibroblast origin (WI-38) all expressed AKT and mTOR protein. BEZ inhibited in vitro cell proliferation of AsPC-1 and HUVECs cells, with some additive effects in combination with Gem or EMAP, after 72 hours of incubation. In AsPC-1, treatment of BEZ (100 nM), Gem (100 nM) and EMAP (1 μM) caused 34, -7, -16, 62, 51, 3, and 59 percent inhibition in proliferation in the B, G, E, B+G, B+E, G+E and B+G+E groups. In HUVECs, percent inhibition in proliferation was 35, 33, 15, 55, 35, 31 and 53 in the B, G, E, B+G, B+E, G+E and B+G+E groups, respectively. Compared to controls (median survival: 16 days), an animal survival increase after BEZ and EMAP therapy alone (both 21 days) and Gem therapy alone (28 d) was observed. Further increases in survival occurred in combination therapy groups B+G (30 d, p=0.007), B+E (27 d, p=0.02), G+E (31 d, p=0.001) and B+G+E (33 d, p=0.004). Conclusions: Bez has experimental PDAC antitumor activity in vitro and in vivo that is further enhanced by combination of Gem and EMAP. These findings demonstrate advantages of combination therapy strategies targeting multiple pathways in pancreatic cancer treatment. No significant financial relationships to disclose.

The PI3K/AKT/mTOR Signaling Pathway: Implications in the Treatment of Breast Cancer

Epidemiologic and experimental studies support a key role of the phosphatidyl inositol 3-kinase/AKT/mammalian target of rapamycin (PI3K/AKT/mTOR) pathway in the biology of human cancers. Alterations resulting in activation of PI3K/Akt/mTOR signaling are perhaps the most frequent events observed in solid tumors, including breast cancer, and contribute to neoplastic transformation. The PI3K/mTOR pathway can be activated by overproduction of growth factors or chemokines, loss of phosphatase and tensin homolog (PTEN) expression, or by mutations in growth factor receptors Ras, PTEN, or PI3K itself. Activation of this pathway contributes to cell cycle proliferation, growth, cell cycle entry, survival, cell motility, protein synthesis, and glucose metabolism, all important aspects of tumorigenesis. The most common genetic aberrations in breast cancer are activating somatic missense mutations in the gene encoding the p110a (PIK3CA) subunit of PI3K. The PTEN gene is often hypermethylated or decreased in expression, through as yet unclear mechanisms, in breast cancer. Studies have shown that PI3K/PTEN/AKT pathway modulation is implicated in HER2/neu-tumorigenesis and in response to the HER2-targeting antibody trastuzumab. Components of the pathway are regulated by feed-back and cross-talk to other signaling cascades and appear to be implicated with drug resistance. Over the past few years, a number of components of this signaling cascade have been the subject of intense drug-discovery activities. Rapamycin analogs have already been shown to have antitumor efficacy in some tumor types. Newer-generation PI3K, AKT, and mTOR inhibitors have shown significant promise preclinically and are now in clinical trials. This article summarizes the progress made in the elucidation of the pathway, clinical implications in pathology of breast cancer, and reviews novel drugs targeting this pathway for cancer treatment, particularly inhibitors of PI3K, AKT, and mTOR, currently undergoing clinical trials. Potential combination strategies, safety concerns, and resistance mechanisms for this new generation of anticancer agents are also discussed.

NF-kappaB in lung cancer, a carcinogenesis mediator and a prevention and therapy target

Lung cancer ranks as the first malignant tumor killer worldwide. Despite the knowledge that carcinogens from tobacco smoke and the environment constitute the main causes of lung cancer, the mechanisms for lung carcinogenesis are still elusive. Cancer development and progression depend on the balance between cell survival and death signals. Common cell survival signaling pathways are activated by carcinogens as well as by inflammatory cytokines, which contribute substantially to cancer development. As a major cell survival signal, nuclear factor-kappaB (NF-kappaB) is involved in multiple steps in carcinogenesis and in cancer cell's resistance to chemo- and radio-therapy. Recent studies with animal models and cell culture systems have established the links between NF-kappaB and lung carcinogenesis, highlighting the significance of targeting NF-kappa signaling pathway for lung cancer treatment and chemoprevention. In this review, we summarize progresses in understanding the NF-kappaB pathway in lung cancer development as well as in modulating NF-kappaB for lung cancer prevention and therapy.

NAMPT overexpression in prostate cancer and its contribution to tumor cell survival and stress response

Nicotinamide phosphoribosyltransferase (NAMPT) is a rate-limiting enzyme in regenerating nicotinamide adenine dinucleotide (NAD(+)) from nicotinamide in mammals. NAMPT has crucial roles for many cellular functions by regulating NAD(+)-dependent SIRT1 deacetylase. However, roles of NAMPT in cancer are poorly defined. In this study, we show that NAMPT is prominently overexpressed in human prostate cancer cells along with SIRT1. Elevation of NAMPT expression occurs early for the prostate neoplasia. Inhibition of NAMPT significantly suppresses cell growth in culture, soft agar colony formation, cell invasion and growth of xenografted prostate cancer cells in mice. NAMPT knockdown sensitizes prostate cancer cells to oxidative stress caused by H(2)O(2) or chemotherapeutic treatment. Overexpression of NAMPT increases prostate cancer cell resistance to oxidative stress, which is partially blocked by SIRT1 knockdown. We demonstrate that in addition to modulating SIRT1 functions, the NAMPT inhibition reduces forkhead box, class 'O' (FOXO)3a protein expression and its downstream anti-oxidant genes catalase and manganese superoxide dismutase. Our results suggest important roles of concomitant upregulation of NAMPT and SIRT1 along with increased FOXO3a protein level for prostate carcinogenesis and their contribution to oxidative stress resistance of prostate cancer cells. These findings may have implications for exploring the NAMPT pathway for prostate cancer prevention and treatment.

Targeting the L-Arginine-Nitric Oxide Pathway for Cancer Treatment

The action of L-arginine is mainly dependent on its end-product, nitric oxide (NO). The L-arginine/NO pathway has been confirmed to play an important role in tumor development. Recent findings indicate that NO derived from L-arginine could influence angiogenesis factors, vascular permeability, perivascular-cell recruitment and vessel remodeling and maturation. Additionally, the L-arginine/NO pathway could activate a broad array of genes that are functionally involved in proliferation, metastasis and apoptosis. Interestingly, this pathway plays roles in both tumorigensis and tumor killing. The role of the L-arginine/NO pathway in tumor therapy has been well-studied. Members of this pathway have been reported to be promising therapeutic molecules in tumor therapy. This review article summarizes research data on the roles of the L-arginine/NO pathway in cancer biology and cancer therapy.

Effects of Rapamycin on Breast Cancer Cell Migration through the Cross-Talk of MAPK Pathway.

Abstract Phase I/II clinical studies with rapamycin analogs in breast and other cancers have demonstrated favorable responses. However, little is known on the effects of the mTOR inhibitor on breast cancer cell metastasis, which is a major cause of morbidity and death. We developed a highly sensitive 3-dimensional (3D) proliferation/invasion assay using quantitative bioluminescence (BL) imaging and applied this assay to evaluate the effects of rapamycin on the triple negative breast cancer cell line MDA-MB231. Without cytotoxicity of rapamycin on this cell line, rapamycin at 10nM inhibited the cell migration/invasion, but not at 1nM and 100nM, which was confirmed by the time-lapse single cell tracking analysis. The quantification of cytoskeleton changes showed most potent effects of 10nM rapamycin on the MDA-MB231 cells, with the formation and rearrangement of specialized cell membrane structures and actin fiber implicated in cell motility. Then, the Panorama Cell Signaling Antibody Microarray, enabling the global comparative analysis of cell signal proteins simultaneously, was exploited to analyze the effects of rapamycin on the cellular signaling network of the MDA-MB231 breast cancer cell line. 100nM rapamycin activated the MAPK pathway obviously, through the attenuated negative feedback of activated S6K1 to PI3K-Raf, which increased the expressions of activated Jun N-terminus kinase (JNK), Erk1/2, MEK-1, Raf-pS621, and MAPK-activated protein kinase 2 (MAPKAPK2) in the cells exposed to 100nM rapamycin. MEK inhibitor U0126 or PD98059 could restore the anti-migration effects of 100nM rapamycin on the MDA-MB231 cells. Furthermore, the combination of MEK inhibitors and rapamycin performed synergism on inhibiting the cell proliferation and migration/invasion. Accordingly, rapamycin at a certain dose suppresses MDA-MB231 cell migration/invasion, and the co-targeting of mTOR and MAPK pathways enhances the inhibition on cell proliferation and migration/invasion, underscoring the potential therapeutic utility of rapamycin, and rapamycin combining with MAPK inhibitors in triple negative breast cancer progression, and the results highlight the cross-talk homeostasis of mTOR and MAPK pathways in cancer treatment. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 5080.

Immunohistochemical detection of poly(ADP-ribose) polymerase inhibition by ABT-888 in patients with refractory solid tumors and lymphomas

Purpose: Targeting the poly (ADP-ribose) polymerase (PARP) pathway for cancer treatment has been an active area of pre-clinical and clinical research. We aimed to determine whether the PARP inhibitor ABT-888 hits its therapeutic target in tumors by immunohistochemistry during a Phase 0 trial conducted at the National Cancer Institute. Experimental design: The expression of poly (ADP-ribose) (PAR) and full size PARP-1 were quantitatively examined by immunohistochemistry in paraffin-embedded tumor biopsies at baseline and 3-24 h after a single oral dose (25 or 50 mg) of ABT-888. Results: Baseline PAR levels were moderate to high in three patients with non-Hodgkin lymphomas, and one each with small cell lung cancer, squamous cell carcinoma of the tongue, and melanoma; low in two patients with cutaneous T cell lymphoma and one with adenocarcinoma of external ear canal. A significant decrease in PAR (median decrease 30.2, range -13.1 to -69.8) was achieved after drug administration (n = 6 pairs; p = 0.03), whereas an increase in PARP-1 expression was observed in five of the six tumors. This resulted in a decrease in the ratio of PAR to PARP-1 in tumor biopsies (median -6.76, range -0.41 to -22.59; p = 0.03). Conclusions: ABT-888 hits its therapeutic target by significantly reducing PAR levels and the ratio of PAR to PARP-1 in human tumor cells detected by immunohistochemistry. Baseline tumor PAR levels vary considerably among patients who entered this phase 0 study. This underscores a need to investigate baseline PAR levels in association with response in future preclinical and clinical studies.

Mapping the information resources available to patients with colorectal cancer

The objectives of this study were to identify gaps in information provision along the colorectal cancer (CRC) treatment pathway as provided by health services within the North Eastern Metropolitan Integrated Cancer Service in Victoria Australia; to evaluate the information and recommend consistent, high quality health information resources; and to recommend strategies to improve delivery of patient information. A random sample of health professionals (n= 47) from various disciplines at eight health service sites participated in semi-structured interviews regarding the types of information they provided to CRC patients. Information items were mapped against a published CRC patient management framework and evaluated. A total of 193 information items were collected with 24 items specific to CRC. Gaps in information provision were evident in the community, at diagnosis, in clinics, when treatment was determined and when completed. The quality of information delivery to CRC patients across the public health sites was variable. Resources were often unavailable, out of date and inaccessible in other languages. Results indicate a need to improve health information availability and resource delivery to all CRC patients across different health services particularly at diagnosis and after treatment. Further research is required to determine patient preferences for information about CRC.

Targeting the Mevalonate Pathway for Improved Anticancer Therapy

The mevalonate pathway is important for the generation of isoprene moieties thereby providing the basis for the biosynthesis of molecules required for maintaining membrane integrity, steroid production and cell respiration. Additionally, isoprene precursors are indispensable for the prenylation of regulatory proteins such as Ras and Ras-homologous (Rho) GTPases. These low molecular GTP-binding proteins play key roles in numerous signal transduction pathways stimulated upon activation of cell surface receptors by ligand binding. Thus, Ras/Rho proteins eventually regulate cell proliferation, tumor progression and cell death induced by anticancer therapeutics. Lipid modification of Ras/Rho proteins at their C-terminal CAAX-box is essential for their correct intracellular localization and function. Therefore, pharmacological inhibition of the isoprene metabolism is anticipated to impact the manifold biological functions attributed to Ras/Rho proteins. Here, the pros and cons of compounds that interfere with the mevalonate pathway for cancer treatment are summarized and discussed.

Common head and neck cancer treatment pathways and associated costs in the U.S. commercial managed care population

e17001 Background: For the treatment of head and neck cancer (HNC), different modalities (chemotherapy, radiation, surgery, or chemoradiotherapy) can be used either independently or in combination with others. Information regarding real-world treatment pattern is limited. The purpose of this study was to identify common treatment pathways and associated costs. Methods: The study was performed using data from a large U.S. commercial managed care claims database. Adult subjects (≥18) diagnosed with HNC between January 1, 2006, to December 31, 2006, (index-period) were identified based on a pre-selected ICD-9-CM codes. All subjects were HNC diagnosis-naïve 12 months prior to their index dates (first date of HNC diagnosis) and followed for 12 months post index date. Treatment modalities were identified based on the Healthcare Common Procedure Coding System used in the U.S. Pathways were constructed by reflecting time of and between modality administration claims. Results: 6,570 subjects were identified. The average age was 61 years (±14.9) and 44% (n = 2869) were female. Midwest (31%) and east (31%) region had a higher (p < 0.01) representation, compared to south (20%) and west (18%). Only 2,257 subjects (34%) received some type of treatment modality and were categorized into 20 mutually exclusive treatment pathways. Of these, 82% (n = 1,843) received single modality, 18% (n = 398) received a combination of 2, and 0.7% (n = 16) received a combination of 3 modalities. Among single modality pathways, radiation (34%; n = 619) was most common, however, cheomoradiotherapy (26%; n = 485) had the highest average patient cost ($98,440). Within double modalities, radiation followed by chemotherapy (24%; n = 95) was most common, however, chemoradiotherapy followed by surgery (4%; n = 16) had the highest average cost ($146,374). Within triple modalities, surgery followed by radiation then chemotherapy (50%; n = 8) was most common and costly ($95,868). Conclusions: The most common treatment pathways one year post HNC diagnosis used a single modality; however, the average patient costs within multiple modalities were higher. Further study is required to investigate if these patterns are comparable to current guideline recommendation. [Table: see text]

DNA Damage Response Pathways in Tumor Suppression and Cancer Treatment

Mammalian cells are frequently at risk of DNA damage from multiple sources. Accordingly, cells have evolved the DNA damage response (DDR) pathways to monitor the integrity of their genome. Conceptually, DDR pathways contain three major components (some with overlapping functions): sensors, signal transducers, and effectors. At the level of sensors, ATM (ataxia telangiectasia mutated) and ATR (ATM-Rad3-related) are proximal kinases that act as the core sensors of and are central to the entire DDR. These two kinases function to detect various forms of damaged DNA and trigger DNA damage response cascades. If cells harbor DDR defects and fail to repair the damaged DNA, it would cause genomic instability and, as a result, lead to cellular transformation. Indeed, deficiencies of DDR frequently occur in human cancers. Interestingly, this property of cancer also provides a great opportunity for cancer therapy. For example, by using a synthetic lethality model to search for the effective drugs, ChK1 inhibitors have been shown to selectively target the tumor cells with p53 mutations. In addition, the inhibitors of poly(ADP-ribose) polymerase (PARP-1) showed selectively killing effects on the cells with defects of homologous recombination (HR), particularly in the context of BRCA1/2 mutations. Since Brit1 is a key regulator in DDR and HR repair, we believe that we can develop a similar strategy to target cancers with Brit1 deficiency. Currently, we are conducting a high-throughput screening to identify novel compounds that specifically target the Brit1-deficient cancer which will lead to development of effective personalized drugs to cure cancer in clinic.

Wealth of opportunity - the C1 domain as a target for drug development.

The diacylglycerol-responsive C1 domains of protein kinase C and of the related classes of signaling proteins represent highly attractive targets for drug development. The signaling functions that are regulated by C1 domains are central to cellular control, thereby impacting many pathological conditions. Our understanding of the diacylglycerol signaling pathways provides great confidence in the utility of intervention in these pathways for treatment of cancer and other conditions. Multiple compounds directed at these signaling proteins, including compounds directed at the C1 domains, are currently in clinical trials, providing strong validation for these targets. Extensive understanding of the structure and function of C1 domains, coupled with detailed insights into the molecular details of ligand - C1 domain interactions, provides a solid basis for rational and semi-rational drug design. Finally, the complexity of the factors contributing to ligand - C1 domain interactions affords abundant opportunities for manipulation of selectivity; indeed, substantially selective compounds have already been identified.

Costs Associated with Diffuse Large B-Cell Lymphoma Patient Treatment in a Canadian Integrated Cancer Care Center

Objective The objective of this study was to provide a detailed comparative microcosting analysis for two cancer treatment pathways to contribute evidence for resource allocation and operational decision-making in a Canadian cancer care context. Methods We estimated direct medical costs (in 2004 CAN$) of the entire pathway of care for diffuse large B-cell lymphoma (DLBCL) patients in a large Canadian cancer treatment center. Patient samples were defined as those who received R-CHOP (rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone; n = 85) or CHOP (i.e., without rituximab; n = 86) as first-line treatment. All subsequent treatments including palliative care for these patient samples were assessed. Hospitalization costs and unit costs of medical resources were collected from integrated medical organizations. Individual patient resource consumption was assessed via medical chart review. Results For first-line treatment, drug cost was the largest contributor to total cost, followed by hospitalization cost. Rituximab was the largest contributor to mean cost differences between R-CHOP and CHOP treatments. For treatments subsequent to first-line treatment, no significant cost differences were found. Hospitalization and transplantation costs were the two largest constituents of total costs subsequent to first-line treatment, followed by drug cost. Patients with advanced stage disease cost significantly more than patients with limited stage disease. Conclusion This is the first detailed microcosting study that has employed consistent local data to estimate total medical costs for DLBCL patients in Canada. This information is useful for resource allocation planning and operational decisions, because it provides more substantive, relevant evidence as compared to aggregated, literature or extrapolated information.

From Nutraceuticals to Pharmaceuticals to Nanopharmaceuticals: A Case Study in Angiogenesis Modulation During Oxidative Stress

This report reviews the potential applications of nanotechnology in various therapeutics and diagnostics areas with special emphasis on key frontiers in angiogenesis modulation using naturally driven drug targets including compounds that modulate oxidative stress and inflammatory pathways for the potential treatment of vascular, cancer, inflammatory, and ocular disorders. Recent advances of the nanotechnology mediated gene delivery are also described in this paper.

Overexpression of PIAS3 Suppresses Cell Growth, Restores the Drug Sensitivity of Human Lung Cancer Cells in Association with PI3-K/Akt Inactivation

Constitutively activated signal transducers, activators of transcription (STAT) are reported to cause uncontrolled transmission of growth signals. In this study, we analyzed the roles of an inhibitor of STAT, protein inhibitor of activated STAT (PIAS) 3, in the development of lung cancer. Treatment with an inhibitor of phosphatidylinositol 3-kinase, LY294002, retarded the growth of human lung cancer cells, rendered them more sensitive to chemotherapeutic agents. However, the inhibition of JAK/STAT by AG490 significantly suppressed cell growth but did not increase drug sensitivity at all. Overexpression of PIAS3 not only significantly inhibited cell growth but also rendered cancer cells up to 12.0-fold more sensitive to the above drugs, which was associated with the suppression of Akt phosphorylation. Inhibition of PIAS3 with small interfering RNA, nevertheless, led cancer cells to accelerate cell proliferation, deteriorate chemosensitivity, augment Akt phosphorylation. Although the overexpression of suppressors of cytokine signaling 3 in cancer cells also inhibited cell growth, STAT3 phosphorylation, it neither increased sensitivity to chemotherapeutic drugs nor affected the phosphorylation of Akt. These results indicate that PIAS3 may be an attractive candidate for targeting the JAK/STAT, PI3-K/Akt signaling pathways in cancer treatment.