Prakash Vishnu

Reversal of the Estrogen Receptor–Negative Phenotype in Breast Cancer and Restoration of Antiestrogen Response

Purpose: In breast cancer, the presence of estrogen receptor α (ER) denotes a better prognosis and response to antiestrogen therapy. Lack of ERα correlates with overexpression of epidermal growth factor receptor or c-erbB-2. We have shown that hyperactivation of mitogen-activated protein kinase (MAPK) directly represses ERα expression in a reversible manner. In this study, we determine if inhibition of MAPK in established ERα− breast cancer cell lines and tumors results in reexpression of ERα, and further, if reexpression of ERα in these ERα− tumors and cell lines could restore antiestrogen responses. Experimental Design: Established ERα− breast cancer cell lines, ERα− breast tumors, and tumor cell cultures obtained from ERα− tumors were used in this study. Inhibition of hyperactive MAPK was accomplished via the MAPK/ERK kinase 1/2 inhibitor U0126 or via upstream inhibition with Iressa or Herceptin. Western blotting or reverse transcription-PCR for ERα was used to assess the reexpression of ERα in cells treated with U0126. Growth assays with WST-1 were done to assess restoration of antiestrogen sensitivity in these cells. Results: Inhibition of MAPK activity in ERα− breast cancer cell lines results in reexpression of ERα; upstream inhibition via targeting epidermal growth factor receptor or c-erbB-2 is equally effective. Importantly, this reexpressed ERα can now mediate an antiestrogen response in a subset of these ERα− breast cancer cell lines. Treatment of ERα− tumor specimens with MAPK inhibitors results in restoration of ERα mRNA, and similarly in epithelial cultures from ERα− tumors, MAPK inhibition restores both ERα protein and antiestrogen response. Conclusions: These data show both the possibility of restoring ERα expression and antiestrogen responses in ERα− breast cancer and suggest that there exist ERα− breast cancer patients who would benefit from a combined MAPK inhibition/hormonal therapy.

TLR2, TLR4 and TLR9 polymorphisms and Crohn's disease in a New Zealand Caucasian cohort.

Background and Aim:  Toll‐like receptors (TLRs) have been identified as susceptibility genes for Crohns disease (CD) in some, but not all, studies. Here we examined the association between candidate disease‐susceptibility polymorphisms in the TLR2, TLR4 and TLR9 genes and CD in a New Zealand Caucasian population.

Update on options for treatment of metastatic castration-resistant prostate cancer.

Background: Prostate cancer is one of the most common cancers in men in US and European countries. Despite having a favorable prognosis, the incidence of incurable metastatic disease and mortality in the US is about 28,000 per year. Although hormone-based androgen deprivation therapies typically result in rapid responses, nearly all patients eventually develop progressive castration-resistant disease state. With readily available prostate-specific antigen (PSA) testing, most of these patients are asymptomatic and manifest progression simply as a rising PSA. In patients with castration-resistant prostate cancer (CRPC), the median survival is about 1–2 years, with improvements in survival seen mostly with docetaxel-based regimens. The purpose of this article is to review the recent developments in the treatment of advanced CRPC. Recent findings: Since the two landmark trials (TAX-327 and Southwest Oncology Group 99–16) in CRPC, several newer cytotoxic drugs (epothilones, satraplatin), targeted agents (abiraterone, MDV3100) and vaccines have been tested in phase II and III setting with promising results. Conclusions: The role of newer agents in the treatment of CRPC still needs to be validated by phase III trials, which are currently ongoing. Whilst the novel biomarkers, ‘circulating tumor cells’, have been shown to provide important prognostic information and are anticipated to be incorporated in future clinical decision-making, their exact utility and relevance calls for a larger prospective validation.

Polymorphisms in the organic cation transporter genes SLC22A4 and SLC22A5 and Crohn's disease in a New Zealand Caucasian cohort.

Polymorphisms in the organic cation transporter (OCTN) genes SLC22A4 (OCTN1; polymorphism 1672C/T) and SLC22A5 (OCTN2; polymorphism −207G/C) at the inflammatory bowel disease (IBD) 5 locus comprise a two‐allele haplotype (SLC22A‐TC) associated with increased risk for Crohns disease (CD). In this study, we examined the contribution of the disease susceptibility haplotype SLC22A‐TC to CD in a New Zealand Caucasian population. The frequencies of the gene polymorphisms 1672C/T and −207G/C were examined in 182 patients with CD and 188 ethnically matched controls by PCR‐RFLP analysis. There was a significant difference in the allele frequency (0.444 vs 0.519; P = 0.041) of the 1672T polymorphism in the SLC22A4 gene between controls and patients with CD. In contrast, there was no significant difference (0.497 vs 0.552; P = 0.135) for the −207C polymorphism in the SLC22A5 gene. The homozygote SLC22A‐TC diplotype was significantly associated with an increased risk for CD (odds ratio 2.19), and the SLC22A‐TC haplotype was associated with increased risk (P = 0.0007) of ileocolonic involvement. The population‐attributable risk for the SLC22A‐TC haplotype is 15.1%. Thus, SLC22A‐TC is associated with an increased risk of CD and disease phenotype in our New Zealand CD cohort.

Efficacy and cost-benefit analysis of risk-adaptive use of plerixafor for autologous hematopoietic progenitor cell mobilization

BACKGROUND: Plerixafor (P) reduces mobilization failure rates but it is very expensive. For better utilization of P, we employed a risk‐adaptive strategy of using it only in patients who are at high risk of mobilization failure, defined by peripheral blood (PB) CD34+ cell count of fewer than 10 × 106/L after 4 days of filgrastim (F) alone.

Current therapeutic strategies for invasive and metastatic bladder cancer

Background Bladder cancer is one of the most common cancers in Europe, the United States, and Northern African countries. Muscle-invasive bladder cancer is an aggressive epithelial tumor, with a high rate of early systemic dissemination. Superficial, noninvasive bladder cancer can most often be cured; a good proportion of invasive cases can also be cured by a combined modality approach of surgery, chemotherapy, and radiation. Recurrences are common and mostly manifest as metastatic disease. Those with distant metastatic disease can sometime achieve partial or complete remission with combination chemotherapy. Recent developments Better understanding of the biology of the disease has led to the incorporation of molecular and genetic features along with factors such as tumor grade, lympho-vascular invasion, and aberrant histology, thereby allowing identification of ‘favorable’ and ‘unfavorable’ cancers which helps a more accurate informed and objective selection of patients who would benefit from neoadjuvant and adjuvant chemotherapy. Gene expression profiling has been used to find molecular signature patterns that can potentially be predictive of drug sensitivity and metastasis. Understanding the molecular pathways of invasive bladder cancer has led to clinical investigation of several targeted therapeutics such as anti-angiogenics, mTOR inhibitors, and anti-EGFR agents. Conclusion With improvements in the understanding of the biology of bladder cancer, clinical trials studying novel and targeted agents alone or in combination with chemotherapy have increased the armamentarium for the treatment of bladder cancer. Although the novel biomarkers and gene expression profiles have been shown to provide important predictive and prognostic information and are anticipated to be incorporated in clinical decision-making, their exact utility and relevance calls for a larger prospective validation.

Safety and Efficacy of nab-Paclitaxel in the Treatment of Patients with Breast Cancer

Taxanes are highly active chemotherapeutic agents in the treatment of early-stage and metastatic breast cancer. Novel formulations have been developed to improve efficacy and decrease toxicity associated with these cytotoxic agents. nab-paclitaxel is a solvent free, albumin-bound 130-nanometer particle formulation of paclitaxel (Abraxane®, Abraxis Bioscience), which was developed to avoid toxicities of the Cremophor vehicle used in solvent-based paclitaxel. In a phase III clinical trial, nab-paclitaxel demonstrated higher response rates, better safety and side-effect profile compared to conventional paclitaxel, and improved survival in patients receiving it as second line therapy. Higher doses can be administered over a shorter infusion time without the need for special infusion sets or pre-medications. It is now approved in the US for treatment of breast cancer after failure of combination chemotherapy for metastatic disease or relapse within 6 months of adjuvant therapy, where prior therapy included an anthracycline. Recently, several phase II studies have suggested a role for nab-paclitaxel as a single agent and in combination with other agents for first-line treatment of metastatic breast cancer.

Polymorphisms of CARD15/NOD2 and CD14 genes in New Zealand Crohn's disease patients.

Polymorphisms in the CARD15/NOD2 gene, which encodes a cytosolic protein involved in bacterial recognition, are associated with development of Crohns disease (CD). Other potential susceptibility genes such as CD14 may compound the risk of developing CD. We examined the frequency of the three major CARD15 risk alleles (3020insC/L1007fsinsC, G908R and R702W), and a functional polymorphism (–159C/T) in the promoter of the CD14 gene in 185 CD patients in New Zealand and 187 ethnically matched controls. The frequencies of the 3020insC (8.1 vs 0.8%, P < 0.0001), G908R (3.5 vs 2.4%, P = 0.37) and R702W (7.3 vs 5.1%, P = 0.21) alleles in CD patients and controls, respectively, were similar to those described in Australia, and the ancestral countries of Scotland, Ireland and the UK. Only the 3020insC polymorphism was found to be a significant risk factor for CD in our New Zealand cohort (odds ratio = 10.91 [95% confidence intervals 3.30–36.08]; P < 0.0001 for heterozygotes), but not a single patient was homozygous for the 3020insC polymorphism. The T allele (51 vs 50%, P = 0.77) and TT genotype (26 vs 24%, P = 0.84) frequencies of the –159C/T CD14 gene promoter polymorphism did not significantly differ between CD patients and controls. In summary, our findings provide evidence that the CARD15 3020insC risk allele influences disease susceptibility in a small proportion (<17%) of New Zealand CD patients, whereas there was no evidence that the CD14 –159C/T polymorphism is associated with CD.

AIDS-Related Non-Hodgkin's Lymphoma in the Era of Highly Active Antiretroviral Therapy

In economically developed countries, AIDS-related lymphoma (ARL) accounts for a large proportion of malignances in HIV-infected individuals. Since the introduction of highly active anti-retroviral therapy (HAART) in 1996, epidemiology and prognosis of ARL have changed. While there is a slight increase in the incidence of Hodgkins lymphoma in HIV-infected individuals, use of HAART has contributed to a decline in the incidence of non-Hodgkins lymphoma (NHL) and also a decrease in the overall incidence of ARL. Strategies that employ HAART, improved supportive care, and the use of Rituximab with multi-agent chemotherapy have contributed to improved rates of complete remission and survival of patients with ARL that rival those seen in stage and histology matched HIV negative NHL patients. Most recent clinical trials demonstrate better outcomes with the use of rituximab in ARL. Tumor histogenesis (germinal center vs. non-germinal center origin) is associated with lymphoma-specific outcomes in the setting of AIDS-related diffuse-large B cell lymphoma. High-dose chemotherapy (HDCT) and autologous stem cell rescue (ASCT) can be effective for a subset of patients with relapsed ARL. HIV sero-status alone should not preclude consideration of ASCT in the setting of ARL relapse. Clinical trials investigating the role of allogeneic hematopoietic stem cell transplant in ARL are currently underway.

IL4 , IL10 , IL16 , and TNF polymorphisms in New Zealand Caucasian Crohn’s disease patients

Dear Editor: Crohn’s disease (CD; OMIM 266600) is a multi-factorial, polygenic disease characterized by differential production of a number of cytokines that potentially contribute to the inflammatory response within the gut. Gene transcription of tumor necrosis factor (TNF; previously known as TNF-α; OMIM 191160; IBD3 locus) is increased in the intestinal mucosa of CD patients even in remission, and high levels of TNF are present in the serum, intestinal mucosa, and stool samples of CD patients. The −308G/A polymorphism (also known as TNF2) in the promoter region of the TNF gene was associated with increased levels of TNF in the plasma of cancer patients [Warzocha et al. (1998) Genetic polymorphisms in the TNF locus influence non-Hodgkin’s lymphoma outcome. Blood 91:3574–3581]. Peripheral blood mononuclear cells from CD patients homozygous for the AA alleles secrete more TNF than those of GG homozygotes, upon stimulation with T cell activators. The A allele is more frequent in subgroups of CD patients with colonic, fistulizing, or steroid-dependent disease. A functional TNF gene polymorphism −863C/A that reduced circulating levels of TNF was positively associated with CD and disease location in Japan [Negoro et al. (1999) CD is associated with novel polymorphisms in the 5′-flanking region of the TNF gene. Gastroenterology 117:1062–1068]. Expression of the pro-inflammatory cytokine interleukin-16 (IL-16; OMIM 603035) is increased in a number of chronic inflammatory diseases including CD. A −295T/C polymorphism in its gene promoter was found to be associated with CD in Germany [Glas et al. (2003) The -295T-to-C promoter polymorphism of the IL-16 gene is associated with CD. Clin Immunol 106:197–200]. Conversely, reduction in expression of the anti-inflammatory cytokine IL-10 (OMIM 124092) is implicated in CD. Administration of recombinant human IL-10 has a clinical benefit to CD patients. Among at least 23 polymorphisms reported in the promoter region of the IL10 gene to date, −1082G/A, −819C/T, and −592C/A, which give rise to three wellconserved haplotypes (GCC, ACC, and ATA) are the most investigated [Turner et al. (1997) An investigation of polymorphism in the interleukin-10 gene promoter. Eur J Immunogenet 24:1–8]. The -1082A allele was significantly associated with decreased IL-10 production in CD patients and controls. The Gly15Arg mutation in the leader sequence of the IL10 gene, which reduces secretion of IL10 by 50%, was present in a family with multiple individuals affected with CD, but not in healthy controls [van der Linde et al. (2003) A Gly15Arg mutation in the interleukin-10 gene reduces secretion of interleukin-10 in Crohn disease. Scand J Gastroenterol 38:611–617]. IL-4 Int J Colorectal Dis (2008) 23:335–337 DOI 10.1007/s00384-007-0338-3