Drive Cancer Growth Research Articles

A phase I study of MM-121 in combination with multiple anticancer therapies in patients with advanced solid tumors.

2609 Background: MM-121 is a fully human monoclonal antibody targeting the epidermal growth factor receptor family member ErbB3. ErbB3 has been implicated in driving cancer growth and in the development of resistance to conventional chemotherapies across multiple malignancies. Here we present results of an open-label, Phase 1, multicenter, non-randomized, dose-escalation trial which recently completed enrollment evaluating MM-121 in combination with one of the following chemotherapies: Gemcitabine (Arm A, n=11), carboplatin (Arm B, n=11), pemetrexed (Arm C, n=10), or cabazitaxel (Arm D, n=11). Methods: Patients were treated in a dose escalation “3+3” design to assess the safety, tolerability and pharmacokinetics (PK) of MM-121 administered weekly in combination with anticancer therapies in subjects with advanced cancer. Doses were escalated until the maximum tolerated dose (MTD) was identified or the combination was shown to be tolerable at the highest planned doses. Secondary objectives included: Determining the objective response rate, clinical benefit rate, PK and immunogenicity of MM-121. Data summarized are as of 1/17/2013 from a live database. Results: Overall, 43 patients, [22 (51%) female and 21 (49%) male] have been treated with a median treatment duration of 57 days (range 1-302). The median age was 59 years (range 42-84) and patients had received a median of four prior lines of therapy (range 0-13). Common (>20%) adverse events of any grade and causality across all arms included diarrhea (74%), nausea (54%), fatigue (51%), anemia (44%), vomiting (33%), hypokalemia (30%), decreased appetite (26%), thrombocytopenia (26%), peripheral edema (23%), neutropenia (21%), and constipation (21%). Four DLTs were observed: Two in combination with carboplatin (G4 thrombocytopenia and G3 rash), one with gemcitabine (G4 thrombocytopenia), and one with pemetrexed (G4 hyperuricemia). Overall 38 (88%) patients were evaluable for response and the overall clinical benefit rate (PR or SD >18 weeks), is 32% (12/38). Conclusions: MM-121 can be combined at its recommended single agent dose with standard doses of gemcitabine, pemetrexed, and cabazitaxel and adapted doses of carboplatin. Clinical trial information: NCT01447225.

Abstract 1412: Cross-species array comparative genomic hybridization identifies novel driver genes in embryonal rhabdomyosarcoma.

Abstract Human cancers are often associated with large chromosomal amplifications and deletions comprising megabases of sequence - making it challenging to identify drivers of cancer growth and progression. To bypass this obstacle, we have applied array comparative genomic hybridization (aCGH) to zebrafish embryonal rhabdomyosaroma (ERMS) and utilized cross-species comparison to identify novel collaborating oncogenes important to human disease. Because zebrafish ERMS predominantly contain small, focal amplifications that span only 50-100kb of sequence, candidate oncogenes were easily identified by cross-species comparisons with human ERMS. Remarkably, 16 of 19 chromosomal gains identified in zebrafish ERMS also exhibited focal, copy gains in human disease. Candidate oncogenes found in these regions were also over-expressed in a majority of human ERMS as assessed by microarray gene expression analysis and immunohistochemical stain of primary human ERMS and normal fetal muscle. siRNA and shRNA knockdown studies identified important roles for candidate ocogenes in regulating human ERMS growth. For example, knockdown of Cyclin D2, Homeobox Protein C6, and Plexin A1 (PLXNA1) resulted in reduced proliferation in both human RD and SMS-CTR cell lines. PLXNA1 knockdown also resulted in impaired migratory potential in scratch and transwell migration assays. Moreover, PLXNA1 loss resulted in increased numbers of terminally-differentiated myosin-expressing myocytes, suggesting that dysregulated expression of PLXNA1 plays a key role in the differentiation arrest of human ERMS. Finally, vascular endothelial growth factor (VEGF) was also amplified and over-expressed in a subset of human and zebrafish ERMS. Chemical inhibition of VEGF in ERMS-bearing zebrafish led to significantly reduced tumor growth which was associated with decreased tumor neovascularization. Analysis of human microarray gene expression data revealed that increased VEGFA expression correlated with poor clinical outcome in patients with ERMS independent of tumor grade and stage, indicating high VEGFA expression as an independent prognostic indicator and implicating inhibitors of the VEGF pathway as a promising therapy for improving patient survival. In total, our results demonstrate the utility of aCGH and cross-species comparisons to rapidly identify candidate genes essential for the pathogenesis of human cancer. Citation Format: Eleanor Chen, Kimberly P. Dobrinski, Kim H. Brown, Ryan Clagg, Elena Edelman, Myron Ignatius, Jillian Brockmann, G. Petur Nielsen, Sridhar Ramaswamy, Charles Keller, Charles Lee, David M. Langenau. Cross-species array comparative genomic hybridization identifies novel driver genes in embryonal rhabdomyosarcoma. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1412. doi:10.1158/1538-7445.AM2013-1412

More patients can benefit from existing breast cancer drugs

Drugs that are highly effective in the treatment of breast cancer can benefit more patients than are currently receiving them, say researchers from Washington University in St. Louis, Missouri. According to a study published in the journal Cancer Discovery, some women with the human epidermal growth factor receptor 2 (HER2)-negative subtype of breast cancer may benefit from anti-HER2 drugs, even though tests do not indicate that they are candidates.1 Women with HER2-positive breast cancer are treated with drugs that inhibit the HER2 protein. These patients may have as many as 20 copies of the gene. To receive the anti- HER2 drugs, patients with breast cancer are tested for this gene “amplification.” However, some patients who have been identified as having HER2-negative disease may have mistakes in just a few “letters” of the DNA in their gene copies that lead to excess activity of the protein. Still, they are not identified as having HER2-positive breast cancer through the testing. Ron Bose, MD, PhD, assistant professor of medicine at Washington University and a coauthor of the study, estimates that these scenarios are undetected HER2 mutations, and that they may effect tumor growth in 1.5% to 2% of all patients with breast cancer. With 230,000 new cases of breast cancer diagnosed annually, that figure translates to more than 4000 patients each year who would benefit from these drugs. The study was led by Matthew Ellis, MD, PhD. He and his colleagues analyzed data from 8 DNA sequencing studies of approximately 1500 patients. Of those, 25 were found to have HER2 mutations without gene amplification. Seven of 13 analyzed mutations were found to drive cancer growth and, in the laboratory, the majority of them responded to the anti-HER2 drugs lapatinib and trastuzumab. Two of the mutations were resistant to lapatinib, but they responded well to neratinib, a newer anti-HER2 drug currently in phase 2 clinical trials. However, some of the mutations studied did not drive the tumor's growth and therefore would not likely respond to the drugs, says Dr. Bose. These findings have led to a phase 2 clinical trial to test whether patients with HER2 mutations (rather than amplification) will benefit from these drugs. The trial will involve patients with stage IV breast cancer whose tumors are classified as HER2 negative. Scientists will sequence the HER2 genes to look for mutations. If they are present, the patients will be treated with neratinib, along with standard treatment. The trial will also include the Dana-Farber Cancer Institute in Boston, Massachusetts, Memorial Sloan-Kettering Cancer Center in New York City, and the University of North Carolina, Chapel Hill.

The TORCH trial.

Non-small cell lung cancer (NSCLC) remains a major cause of cancer-related death worldwide (1). Unfortunately the majority of patients are diagnosed with advanced disease where the treatment intent is palliative. The mainstay of treatment, until recently, has been platinum based doublet chemotherapy which improves symptoms and prolongs survival compared to best supportive care (2). Increased interest in the molecular pathways which drive cancer growth has led to the development of targeted agents such as the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) erlotinib and gefitinib which are both approved for use in first-line for advanced NSCLC harbouring an EGFR activating mutation and as secondor third-line treatment (erlotinib) for advanced NSCLC, independently of the EGFR mutational status.

Rescue Screens with Secreted Proteins Reveal Compensatory Potential of Receptor Tyrosine Kinases in Driving Cancer Growth

The overall power of kinase inhibitors is substantially overshadowed by the acquisition of drug resistance. To address this issue, we systematically assessed the potential of secreted proteins to induce resistance to kinase inhibitors. To this end, we developed a high-throughput platform for screening a cDNA library encoding 3,432 secreted proteins in cellular assays. Using cancer cells originally dependent on either MET, FGFR2, or FGFR3, we observed a bypass of dependence through ligand-mediated activation of alternative receptor tyrosine kinases (RTK). Our findings indicate a broad and versatile potential for RTKs from the HER and FGFR families as well as MET to compensate for loss of each other. We further provide evidence that combined inhibition of simultaneously active RTKs can lead to an added anticancer effect.

974PD - A Phase 1 Study of the Anti-Erbb3 Antibody Mm-121 in Combination with Weekly Paclitaxel in Patients with Advanced Gynecological and Breast Cancers

ABSTRACT Background MM-121 is a fully human monoclonal antibody targeting the epidermal growth factor receptor family member ErbB3. ErbB3 has been widely implicated in driving cancer growth and in the development of resistance to conventional chemotherapies and targeted agents across multiple malignancies. Single agent weekly paclitaxel is a standard regimen for patients with advanced gynecological and metastatic breast cancers. Here we present results from an ongoing Phase 1 study evaluating the combination of MM-121 and weekly paclitaxel. Methods A total of 24 patients with either platinum resistant ovarian cancer, metastatic endometrial cancer, or HER2 negative metastatic breast cancer, were treated in a dose escalation (12 pts) or expansion cohort (12 pts). Patients were treated until disease progression or intolerable toxicity. Response was assessed every eight (8) weeks according to RECIST 1.1. In the dose-expansion cohorts, pre- and post-treatment fresh tumor biopsies were obtained from 12 patients to assess ErbB3 signaling status and its potential as a predictive marker for MM-121 response. Results To date, 24 patients have been treated with a median follow up of 5.5 months (range 0.8 – 13.1). The median age was 58 years (range 38 – 72), and patients had received a median of four (range 1 – 11) prior lines of therapy. Common (>20%) adverse events of any grade included fatigue (62%), peripheral neuropathy (58%), diarrhea (46%), neutropenia (46%) and rash (38%). Grade 3/4 toxicities included fatigue (17%), peripheral neuropathy (8%), diarrhea (12%), neutropenia (16%), anemia (4%), abdominal pain (8%), and hypokalemia (4%). 17 (71%) patients were evaluable for response and the overall clinical benefit rate, defined as PR or SD lasting for >4 months, was 71%. 47% achieved a PR and 35% a confirmed PR with a median duration of response of 4.6 months (range1.7 – 9.6) and 24% had SD >4 months with a median duration of SD of 5.6 months (range 4.2-12.6). 17% patients had PD at first assessment and 38% remain on study with a median on-study time of 10.2 months (range 1.4 – 13.1). Translational analyses exploiting tissue analysis in combination with in silico modeling are ongoing. Conclusion The combination of MM121 and paclitaxel showed activity in metastatic ovarian and breast cancers. Disclosure J. Liu: Joyce Liu is an investigator participating in the corporate-sponsored study which is the subject of the abstract. R. Patel: Ravi Patel is an investigator participating in the corporate-sponsored study which is the subject of the abstract. G. Kato: Giraldo Kato is an investigator participating in the corporate-sponsored study which is the subject of the abstract. U. Matulonis: Ursula Matulonis is an investigator participating in the corporate-sponsored study which is the subject of the abstract. V. Moyo: Victor Moyo is employed by and owns stock in the corporate sponsor of this reserach. K. Riahi: Kaveh Riahi is employed by and owns stock in the corporate sponsor of this research. J. Pearlberg: Joseph Pearlberg is employed by and owns stock in a corporate sponsor of this research. A. Czibere: Akos Czibere is employed by and owns stock in the corporate sponsor of this research. S. Isakoff: Steven Isakoff is an investigator participating in the corporate-sponsored study which is the subject of the abstract. He has also served as a consulant to Merrimack Pharmaceuticals.

Correlation of markers of oxidative damage and circulating IL6 levels with survival following treatment with bevacizumab in metastatic colorectal cancer patients.

e21024 Background: Angiogenesis drives cancer growth, tumour progression and metastases. Hypoxic tumours initiate recruitment of their own blood supply and enhance expression of vascular endothelial growth factor (VEGF). Bevacizumab is a recombinant humanised monoclonal anti-VEGF antibody which prevents VEGF binding to its receptors and improves overall survival in metastatic colorectal cancer patients when combined with cytotoxic chemotherapy. Currently, Bevacizumab is indicated as a first line treatment in all metastatic colorectal cancer patients, however only 38-44% of these patients will have a response to treatment. There is no good marker to predict treatment response. The role of inflammation and oxidative damage in driving angiogenesis and clinical response to bevacizumab is poorly understood. The aim of this study was to investigate the levels of oxidative damage and inflammation in the tissue and in the circulation of patients receiving Bevacizumab. Methods: Tissue from 80 patients was constructed into tissue microarrays (TMAs) and screened by immunohistochemistry for the levels of a DNA adduct marker 8oxodG and a lipid peroxidation marker 4HNE in addition to Ki67 status. Serum was screened for 8oxodG, 4HNE and the inflammatory cytokines; IL1β, IL6, IL8, TNFα and pro-angiogenic factors; Ang 2, TGFβ, VEGF using ELISA. Data was correlated with patient survival following Bevacizumab treatment. Results: 8oxodG stromal nuclear positivity significantly correlated with survival following bevacizumab (p=0.035) and this was independent of cell proliferation status. Following multivariate analysis, circulating IL6 levels also significantly correlated with survival following bevacizumab treatment (p=0.01). Using linear regression, circulating levels of 8oxodG correlated with IL6 levels (p=0.016). Circulating Ang 2 levels correlated with IL6 (p=0.006). Conclusions: We have shown for the first time that levels of a DNA adduct marker 8oxodG and circulating levels of IL6 correlate with survival in metastatic patients receiving Bevacizumab.

Regulation of intestinal cancer stem cells

Colorectal tumours harbour a sub-population of cells with stem like properties termed ‘cancer stem cells’, which are believed to ultimately drive cancer growth. This review discusses recent advances in our understanding of both normal and cancer intestinal stem cells, with emphasis on similarities and differences. Specifically we discuss the role of the Wnt, Notch and BMP pathways and their roles in both stem cell proliferation and differentiation. Furthermore we discuss the emerging role of microRNA and the influence of environmental factors such as tumour associated myofibroblasts and hypoxia on cancer stem cell regulation.

Upregulation of Trop-2 quantitatively stimulates human cancer growth

Trop-2 is a calcium signal transducer that is associated with transformed cell growth in experimental systems. However, its role in human cancer remains essentially unknown. In this study, we profiled Trop-2 expression in normal human tissues at the mRNA and protein levels. We then systematically compared Trop-2 mRNA and protein levels in tumours with their tissues of origin. We find that Trop-2 expression is invariably upregulated in tumours, regardless of baseline expression in normal tissues, which suggests a corresponding selective advantage. Thus, we investigated the outcome of Trop-2 upregulation on tumour growth. Overexpression of wild-type Trop-2 was shown to be necessary and sufficient to drive cancer growth in a widely invariant manner across cell type and species. Upregulation of Trop-2 was shown to quantitatively stimulate tumour growth, as proportional to expression levels in vivo, and tumour cell growth was abrogated by somatic knockdown of Trop-2 expression. On the other hand, we found no evidence of tumour-associated TROP2 mutations, nor of TROP2 induction of oncogenic transformation per se. Our data support a model where above-baseline expression of wild-type Trop-2 is a key driver of human cancer growth.

Managing immunity in resistant cancer patients correlates to survival: results and discussion of a pilot study.

Many cancer patients do not die due to impaired organ functions, but as a result of reduced general conditions, such as cachexia, sarcopenia, depression, infections, or stress. Reduced general health may be caused by immune modifying cytokines released from the tumor into the body. Improvement of immunity would not only reduce cancer side effects through inhibiting cytokine release from the tumor into the blood, but also, according to a new hypothesis, modify the cancer stem cells (CSC) in the tumor, which are believed to drive cancer growth and metastasis. We reported previously several investigations with a dietary fermented soy formulation (FSWW08) in cancer patients, where we saw a) strong reduction of cancer symptoms, b) broken resistance to chemotherapy, and c) a strong reduction of chemotherapy's toxic side effects, when taken in combination. This publication reports two new findings from a pilot study with postsurgical, treatment resistant patients conducted over four years. First, neither treatment resistance nor side effects were observed. Second, more patients have survived than expected. The improved health and immunity is detected together with increased CSC differentiation, suggesting lower aggressiveness, which was corroborated by increased gene expressions, particularly of steroidal hormones, MAPkinase, NF-κB, and tumor suppressor factor p53, a typical marker of "stemness" or cell differentiation. Although limited by its small, homogenous sample size, the results of this pilot study illustrate the relationship between CSCs differentiation, and the clinical symptoms of immunity, which influence survival outcomes and raise the clinical potential of measuring CSCs in ovarian, prostate, and breast cancers. The improved survival rates are also seen in larger cohort studies, which show similar gene expression profiles, which were induced by FSWW08 in the treatment resistant cancer patients in this study.

The Drug-Induced Degradation of Oncoproteins: An Unexpected Achilles' Heel of Cancer Cells?

Many targeted therapies against cancer are aimed at inhibiting the enzymatic activity of kinases. Thus far, this approach has undoubtedly yielded significant clinical improvements, but has only rarely achieved cures. Other drugs, which selectively elicit proteasome-dependent degradation of oncoproteins, induce the loss of cancer cell self-renewal and promote cell differentiation and/or apoptosis. In acute promyelocytic leukemia, the cooperative degradation of PML/RARA by arsenic and retinoic acid cures most patients. In this condition and others, drug-induced proteolysis of oncoproteins is feasible and underlies improved clinical outcome. Several transcription factors, nuclear receptors, or fusion proteins driving cancer growth could be candidates for proteolysis-based drug-discovery programs.

Abstract 1724: Inhibition of the PI3K and mTOR pathways reverses gemcitabine resistance in pancreatic cancer

Abstract BACKGROUND: Despite chemotherapy, survival for most patients with pancreatic cancer is less than one year. These dismal statistics reflect the lack of effective therapy. Understanding the molecular pathways that drive cancer growth may help target our therapy. Over 90% of pancreatic cancers are K-ras mutant which activates the PI3K/AKT pathway and signals downstream to mTOR leading to cell growth, proliferation and survival. We explored the combination of gemcitabine and BEZ235, a novel dual PI3K/mTOR inhibitor, in pancreatic cancer cell lines. METHODS: Cytotoxicity assays were performed utilizing the CellTiter-96-Aqueous-One-Solution-Cell-Proliferation-Assay-(MTS) from Promega in K-ras mutant MIA PaCa-2 pancreatic cancer cell lines. We generated gemcitabine resistant cell lines by serial passage of cells with increasing concentrations of drug. We utilized the CalcuSyn program by Biosoft to quantify synergism or antagonism with drug combinations. We also collected cells 6 hours after drug treatment for analysis of phosphorylated proteins. RESULTS: MIA PaCa-2 wild-type and gemcitabine resistant cells were treated with 100, 50 and 25 nM of either gemcitabine, BEZ235 or the combination of both. At the 100 nM dose, cell viability of the wild-type cells was 66%, 55% and 39% respectively. In the gemcitabine resistant cells, cell viability was 84%, 63% and 44%. The combination index was 0.51 in the wild-type cells and 0.46 in the gemcitabine resistant cells indicating synergy in both cell lines. In both cell lines, p-S6K and p-AKT levels increased with gemcitabine treatment which was abrogated by treatment with BEZ-235. Interestingly, in the gemcitabine resistant cells, there appeared to be significantly increased levels of p-MEK1 compared to control. CONCLUSION: Because pancreatic cancer remains resistant to current therapies despite recent advances in the development of molecular targeted therapies, there is an urgency to understand these pathways. We showed that the combination of gemcitabine and BEZ235 is synergistic in both cell lines but cell viability still remains high at 39% and 44% respectively. Combination with a MEK inhibitor may help to increase cell apoptosis and studies are on-going. 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 1724. doi:10.1158/1538-7445.AM2011-1724

GISTIC2.0 facilitates sensitive and confident localization of the targets of focal somatic copy-number alteration in human cancers

We describe methods with enhanced power and specificity to identify genes targeted by somatic copy-number alterations (SCNAs) that drive cancer growth. By separating SCNA profiles into underlying arm-level and focal alterations, we improve the estimation of background rates for each category. We additionally describe a probabilistic method for defining the boundaries of selected-for SCNA regions with user-defined confidence. Here we detail this revised computational approach, GISTIC2.0, and validate its performance in real and simulated datasets.

Comparison of signal transduction drug response markers in immortalized cell lines and primary patient specimens

Abstract Background: The epidermal growth factor pathway is an important driver of cancer growth. Erlotinib is a small molecule protein-kinase inhibitor targeting the epidermal growth factor receptor (EGFR) that may benefit a select subtype of cancer patients. However, identification of the characteristics of patients who may benefit from the use of erlotinib is not easy. Previous publication explored the activation of signal transduction proteins in the EGFR pathway as a method of determining erlotinib response and demonstrated that lung cancer cell lines characterized by increased pEGFR/pAKT ratios are more resistant to erlotinib. The aim of this study was to compare the activation of signal transduction markers in the EGFR pathway between immortalized cell lines and primary cultures of patient-derived tumor cells. Predictive potential of pEGFR/pAKT ratios in both immortalized cell lines and primary cultures of lung cancer cells was also compared. Methods: Western blotting and In-Cell western analysis were used to determine the activation state of the EGFR signaling pathway. Signaling pathway components were compared in the presence and absence of erlotinib treatment in immortalized lung cancer cell lines and primary cultures of lung cancer specimens. Chemosensitivity of cell lines and specimens to erlotinib was determined using an in vitro drug response marker. Cells were treated with a 10 dose concentration range of erlotinib for 72 hours and the remaining post-treatment live cells were enumerated by nuclear staining. Results: The pEGFR/pAKT ratio was increased in erlotinib-responsive immortalized cell lines when compared to non-responsive cell lines (p<0.05). This difference in pEGFR/pAKT ratio was significant after treatment with erlotinib as well. The difference in pEGFR/pAKT ratios in response to erlotinib treatment between erlotinib-responsive and non-responsive primary cultures of lung cancer cells was not, however, statistically significant. Conclusion: These studies confirmed that pEGFR/pAKT ratios may be indicative of erlotinib response in immortalized lung cancer cell lines. However, when evaluating the signal transduction markers in patient-derived primary cultures, no correlation with in vitro erlotinib response was found. These results highlight the value of using in vitro drug response markers, which utilize primary patient tissue, in the development of predictive biomarkers.

Spotlight

Wang et al., pp. 599–610 Prostate cancer often lingers at a relatively benign stage for many years, only to suddenly erupt into evasive, deadly disease that spreads throughout the body. During the disease's progression, stromal cells, which form the supportive network of the prostate gland and engage in constant crosstalk with neighboring cells, start releasing high levels of growth factors, which work together to promote tumor growth. To do so, they require stimuli from epithelial cancer cells but the precise mechanism is poorly understood. Recently, the authors and others found that prostate-specific tissue kallikrein 4 (KLK4) is a potential activator of protease-activated receptors (PARs) 1 and 2, which are G-protein-coupled receptors implicated in various cancers. Since PAR-1 is characteristically localized in peritumoral stromal cells, Wang et al. explored the possibility that epithelial cancer cells can stimulate stromal cells through PAR-1 activation to result in the release of growth factors and cytokines that drive cancer growth. Their experiments uncovered a novel double-paracrine feedback loop initiated by KLK4, which is produced exclusively by prostate epithelium. KLK4 activates PAR-1 on prostate stromal cells, which in turn induces stromal cells to release numerous cytokines, including IL-6. Upon binding to its receptors on cancer cells, IL-6 signaling activates androgen-regulated genes such as PSA and KLK4 via STAT3 or MAPK pathways, closing the loop. Uncovering the various communication channels between prostate tumor cells and their microenvironment may lead to novel therapeutic approaches based on interrupting tumor-stroma interactions. Sun et al., pp. 764–774 Desiniotis et al., pp. 775-789 The growth of prostate cancer is fueled by the androgen receptor (AR), a transcription factor that binds steroid hormones, coactivators and coreceptors of AR, and then translocates to the cell nucleus where the AR-complex activates a number of androgen-responsive genes. Consequently, for the last 70 years the treatment of choice for advanced metastatic prostate cancer has been androgen deprivation therapy. But inevitably, in patients treated with hormonal therapy the tumor becomes androgen-independent; yet these tumors retain their dependence on AR signaling even after they become androgen-independent. Two reports in this issue focus on strategies aimed at intercepting AR signaling by removing the receptor itself from the cells. Sun et al. generated an adeno-associated virus (AAV) vector to express a short hair-pin-structured RNA directed against the AR gene (ARHP8), which induces apoptotic cell death in AR-positive prostate cancer cells in vitro as they had previously shown. When delivered via tail vein injection into prostate cancer xenograft-carrying mice, ARHP8 dramatically reduced AR gene expression, induced apoptotic cell death and eliminated xenograft tumors within 10 days. The authors of the second study, Desiniotis et al., went a step further and simultaneously inhibited AR and cAMP-dependent protein kinase A (PKA) with small interference RNAs. Overexpression of PKA's regulatory subunit PKA RIα has been strongly associated with tumor progression and poor prognosis and can activate AR via crosstalk in a ligand-independent manner. Inhibition of both AR and PKA RIα expression with antisense molecules significantly enhanced the anti-proliferative and proapoptotic effects of AR knockdown in androgen-sensitive and in AR ablation-resistant prostate cancer cells. Taken together, these results demonstrate that novel therapeutic strategies targeting AR signaling offer promising potential for the treatment of hormone refractory prostate cancer. Renehan et al., pp. 692–702 “… with more than half of all adult Europeans overweight or obese the absolute number of cancer cases that can be blamed on excess body weight could be substantial.” It's been well known that extra body fat increases the risk of developing cancer. Although the risk per 5 kilogram-per-meter-squared increase in body mass index (BMI) is modest, with more than half of all adult Europeans overweight or obese, the absolute number of cancer cases that can be blamed on excess body weight could be substantial. And the numbers are only expected to increase as people continue to eat more and exercise less. To establish a baseline for modeling future trends and interventions, Renehan et al. estimated how much of the cancer burden can be attributed to excess body mass index (BMI) in 30 European countries, drawing upon a previously published meta-analysis. Their study revealed that 2.5% of all new cancer cases in men and 4.1% of all new cancer diagnoses in women were directly related to being overweight (BMI ≥ 25). These collectively corresponded to 70,288 new cases, with endometrial, postmenopausal breast and colorectal cancers accounting for 65% of the total. These results have important implications for setting future research priorities and national health policy as obesity-related cancer affects more women than men and, on a country level, is a greater problem in Central European Countries such as the Czech Republic than for Scandinavian countries such as Denmark.

A synergistic suppression of aromatase by letrozole and the DAC inhibitor panobinostat (LBH589), an inhibitory modulator of aromatase gene expression.

Abstract Abstract #3062 Background. The human aromatase gene contains nine translated exons (II-X) and at least eight tissue specific untranslated exon Is (I.1, I.2, I.3, I.4, I.5, I.6, I.7 and PII). Eight different promoters are located immediately upstream of the corresponding exon I's, and each promoter is regulated by different mechanisms. Previous studies have revealed that exons I.3 and PII are the major exon Is in aromatase mRNA isolated from breast cancer tissue, indicating that aromatase expression in breast cancer is mainly driven by promoters I.3 and II. In normal breast stromal cells and bone tissue, promoter I.4 is the major promoter driving aromatase expression. Furthermore, breast intra-tumor estrogen levels have been shown to play more important roles than circulating estrogens. Therefore, the potential for selective suppression of aromatase expression/estrogen biosynthesis in breast cancer tissues through the down-regulation of breast tumor-specific I.3/II promoters would be a novel approach to possible reduce side effects associated with whole-body suppression of estrogen biosynthesis achievable with aromatase inhibitors (AIs). Results. Our recent research has found that the DAC inhibitor panobinostat is a potent inhibitor of aromatase expression (IC50 = 15 nM; panobinostat is 40 times more potent than SAHA). Panobinostat has been previously found to induce the degradation of proteins driving cancer growth and is currently in Phase II/III clinical development in patients with cutaneous T-cell lymphoma (CTCL). Our results also indicate that panobinostat selectively suppresses the promoters I.3/II of the human aromatase gene. Furthermore, using the H295R cell culture model, we observed that to achieve the same degree of inhibition of aromatase activity, the needed concentration of letrozole (LET; an AI), in the presence of 25 nM panobinostat, was one fifth that required in the absence of panobinostat. Aromatase expression in H295R cells is selectively driven by promoters I.3/II. In addition, cell culture experiments were performed using a H295R/MCF7 co-culture model that demonstrated the synergistic interaction of panobinostat + LET in suppressing the proliferation of hormone-responsive breast cancer cells. Finally, our preliminary results indicate that panobinostat down-regulates the activity of aromatase promoters I.3/II through an epigenetic mechanism, possibly via the acetylation of C/EBPδ which upregulates breast cancer-specific aromatase promoters I.3/II. Discussion. Panobinostat is the first drug identified to selectively suppress the breast cancer-specific aromatase promoters I.3/II and, not other promoters used to drive aromatase expression in non-cancerous tissues. While experiments are being performed to clearly define the molecular mechanisms involved, the results demonstrating synergistic interactions between panobinostat and LET in modifying breast cancer cell proliferation may hold potential value for future clinical evaluation of these agents in combination. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 3062.

Individualised cancer therapeutics: dream or reality?

Traditional measures for treating metastatic cancer involve identification of the originating organ from which the neoplasm arose and empirical treatment with cytotoxic chemotherapy. Arguably, with the exception of haematological malignancies, demonstration of efficacy in solid tumours has been limited. Over the past half-decade, theoretical and technological advances have resulted in greater application of molecular science to drug design, which has enabled development of new ‘targeted’ therapeutics. However, generic chemotherapy paradigms have not changed. Establishment of the optimal population for ‘targeted’ therapeutics based on molecular diagnostics (i.e. genomic and proteomic characterisation) to identify sensitive tumour–host ecosystems in individual patients at the ‘bedside’, is not being done as part of routine oncology management. This review focuses on the concept of designing individualised therapeutics based on genomic and proteomic profile of malignant tissue. Genetic and epigenetic perturbations in signal pathways drive cancer growth, survival, invasion and metastatic spread. The burgeoning evidence which supports the concept that each patient’s cancer has a unique complement of pathogenic genetic and molecular derangements is reviewed. Such evidence supports the strategy of individualised selection of a therapeutic complex from a menu of targeting options that best complements the specific oncomolecular profile of the ‘tumour–host’ system.

Making sense of antisense

The specific and rational targeting of key genes, identified to be vital to driving cancer growth, has recently led to the successful development of several small molecule and antibody therapeutics. However, despite considerable efforts, antisense oligonucleotides (ASO) have yet to prove their worth as targeted therapies. However, many important genes cannot be readily targeted by antibodies or small molecules, and could be blocked by ASOs. Moreover, the latest generation of ASOs is safe, well tolerated and able to modulate target protein expression both in surrogate and tumour tissue in the clinic. This review will describe the experience acquired with these agents to date and will raise critical issues relevant to the further optimal development of these agents. Future clinical studies need to evaluate combinations of several different ASO targeting multiple key targets, including strategies that reverse functional redundancy of the key target ( e.g., targeting several Bcl family members including Bcl-2 and Bcl-x). Approaches to maximise the duration of target blockade yet avert the need for prolonged intravenous infusions, with the consequent risk of line infection and thrombosis, are also needed. These may include slow-release depot subcutaneous formulations. Short interfering (Si) RNA therapeutics, which are now being evaluated in early clinical trials, are also envisioned to impact the future utility of this class of therapeutics. The high manufacture cost of these agents, when compared with small chemical molecules, could however, limit their success unless cost-effective manufacturing processes are developed.

Mode of action of docetaxel – a basis for combination with novel anticancer agents

Different tumors have different aberrations in signaling and growth stimulation pathways that drive cancer growth. An understanding of these processes is key to the development of new anticancer agents and to identifying optimal treatment strategies and patient populations suitable for specific therapies. It is becoming clear that certain chemotherapeutic drugs such as docetaxel are not simply inhibitors of mitosis and may interact with these tumorigenic mechanisms at a number of levels. This review describes docetaxel’s mechanism of action, and provides a basis for understanding how its antitumor activity can integrate with that of different novel agents. Against this background, key docetaxel–novel agent combinations that are currently under clinical investigation are reviewed. How these strategies can be targeted towards specific patient populations ( e.g., HER-2 overexpressing metastatic breast cancer patients) to provide optimal therapy is highlighted.