Scientists at Weill Cornell Medical College (NY, USA) have identified two cellular receptors that likely contribute to the genesis of hormone-dependent breast cancer, potentially paving the way for new, highly targeted therapies against the disease.
“These two receptors, called EP2 and EP4, form key links in a biochemical pathway that boosts estrogen production in fat and breast cancer cells – this, in turn, may increase a woman’s risk for developing hormone receptor-positive breast cancer. Finding ways to interrupt this pathway in a manner that causes few side effects is the ultimate goal of this research,” explains senior author Dr Andrew Dannenberg.
Approximately 75% of all breast malignancies are estrogen receptor positive, and it is for this reason that anti-estrogen drugs such as tamoxifen and aromatase inhibitors have come to the forefront in the fight against hormone-dependent breast cancer. “Cancer researchers have for years been exploring the pathway by which aromatase is regulated. We know that if you reduce aromatase activity that you also reduce levels of cancer-causing estrogen in breast tissues” explains lead author Dr Kotha Subbaramaiah.
Dr Dannenberg’s team previously demonstrated that COX protein-derived prostaglandin E2 (PGE2) could turn on the gene that expresses aromatase. More recently, the healthy form of the BRCA1 tumor-suppressor gene was found to silence the aromatase gene – performing its duty in keeping breast cancer risk low.
“Maintaining this BRCA1-aromatase relationship in a healthy balance may help to keep patients free of hormone-dependent breast cancer,” Dr Dannenberg explains.
Studies have shown that use of NSAIDs can also dampen PGE2 production and aromatase activity. COX-2 inhibitors (which include Vioxx and Celebrex) may do the same. However, these drugs also suppress a prostanoid that helps protect the heart, and, crucuially, Vioxx was withdrawn from the market due to an excess of cardiovascular events noted in long-term users.
“So, we are always looking for other points in the prostaglandin – aromatase – estrogen pathway that can shield women from breast cancer without raising risks in other areas,” Dr Dannenberg says.
That’s one of the reasons the results of the new study are intriguing.
Using experiments conducted in cell culture and in the mammary tissues of mice, the Weill Cornell team discovered that the two cellular receptors – EP2 and EP4 – switch on a complex biochemical pathway that activates the aromatase gene.
“It appears that PGE2 binds to these receptors and that this causes a downregulation of BRCA1. As we already know, less BRCA1 means more aromatase activity to produce estrogen, and that could mean a higher risk for estrogen-receptor-positive cancer” Dr Subbaramaiah states.
The team found that EP2 and EP4 performed in this way in both adipocytes and in breast cancer cells. This could be important for both the development and growth of breast cancer. “We also validated the presence of this pathway in an animal model, the first time that’s ever been done,” Dr Dannenberg notes.
The finding has many potential implications. Firstly, it adds valuable new information to the study of hormone-dependent breast cancer generally, and secondly, the receptors offer brand new targets for pharmaceutical research. “In fact, drugs that work against EP2 and EP4 (‘antagonists’) are already in development by pharmaceutical companies,” Dr Subbaramaiah says. “Our confirmation of the receptors’ key role in regulating aromatase activity supports the further development of this form of targeted therapy.”
Source: Subbaramaiah K, Hudis C, Chang SH, Hla T, Dannenberg AJ. EP2 and EP4 receptors regulate aromatase expression in human adipocytes and breast cancer cells. Evidence of a BRCA1 and p300 exchange. J. Biol. Chem. 83(6), 3433-3444 (2008).
T-cell immunotherapy shows promise for HER-2 metastatic breast cancer
In a case study published in Cancer Immunology, Immunotherapy it has been demonstrated that breast cancer patients with metastatic disease resistant to anti-HER-2 therapy could be treated with adoptive T-cell transfer to target and destroy disseminated tumor cells.
Lead author Helga Bernhard (Technical University of Munich, Germany) and colleagues describe how there is growing evidence that the presence of T lymphocytes in the vicinity of a tumor correlates with a favorable prognosis. However, as the authors explain, a tumor has the ability to circumvent the host’s immune attack via a process known as tolerance induction.
One type of experimental approach to overcome such tolerance is to remove potentially tumor-reactive T cells from a patient and then artificially stimulate these cells ex vivo and reintroduce them into the patient. In the present study, researchers identified three breast cancer patients who had developed distant metastases and disseminated tumor cells at several sites including liver, lung, bone marrow, lymph nodes, and brain.
HER-2 overexpression was demonstrated in both primary tumor and distant disease sites, however, patients were refractory to standard regimens including surgery, radiotherapy, chemotherapy, HER-2 monoclonal antibody therapy, and combined modalities.
Taking blood samples from the patients, Bernhard et al. were able to isolate, stimulate, and clone T cells directed against HER-2 tumor cells using dendritic cells loaded with human leukocyte antigen-A2-binding peptide HER-2369-377. The expanded and primed population of anti-HER-22 T cells was then infused in patients and visualized using a radioactive tracer. These T cells honed directly to the sites of distant disease and, furthermore, they appeared to target and destroy disseminated tumor cells. Incredibly, the concentration of disseminated tumor cells in bone marrow was 256 per 106 mononuclear cells prior to adoptive T-cell transfer, dropping to an undetectable 0 cells per 106 mononuclear cells after the transfer.
Summarizing their findings, Bernhard and colleagues conclude: “This study suggests the therapeutic potential for HER-2-specific T cells for eliminating disseminated HER-2-positive tumor cells and proposes the combination of T-cell-based therapies with strategies targeting the tumor stroma to improve T-cell infiltration into solid tumors.”
Source: Bernhard H, Neudorfer J, Gebhard K et al. Adoptive transfer of autologous, HER2-specific, cytotoxic T lymphocytes for the treatment of HER-2-overexpressing breast. Cancer Immunol. Immunother. 57, 271-280 (2008).
Small-molecule drug designed to activate p53 protein
Researchers have long searched for a novel cancer drug that activates p53, enabling it to kill tumor cells without causing damage to normal cells. Scientists at the University of Michigan Comprehensive Cancer Center (MI, USA) have now designed a small molecule that is highly effective in cell cultures at inhibiting the interaction between p53 and MDM2, a protein that inactivates p53 in cancer.
“For more than 10 years scientists have searched for ways to block p53 inhibition, but with little success. Our study clearly shows that this can be done,” says study author Shaomeng Wang.
In normal situations, p53 helps suppress tumors, but it is inactivated in almost all human cancers, often as a result of its binding to MDM2, which inhibits p53’s tumor suppressor function, promoting cancer development.
Using a computer-assisted approach, researchers designed a small molecule, called MI-219, which is highly effective in blocking the interaction of MDM2 and p53. MI-219 specifically kills tumor cells by harnessing the power of p53. In animal models of human cancer, MI-219 completely inhibited tumor growth and appeared to cause no toxicity. “Many traditional cancer drugs also activate p53 but they do so by causing DNA damage. MI-219 is unique in that it is designed to activate p53 without causing DNA damage, specifically killing tumor cells. Indeed, MI-219 is highly effective in inhibiting tumor growth, and even inducing tumor regression, but it has caused no toxicity to animals at efficacious doses,” says Wang.
In addition to its effectiveness at killing cancer cells without toxic side effects, the new molecule may be ideal for drug development as it can be given orally as a pill, compared with traditional chemotherapy drugs that must be given intravenously at a hospital or cancer center.
However, Wang has cautioned, “While promising in preclinical studies, MI-219 needs to be evaluated in human clinical trials for its safety and efficacy for cancer treatment since it is a brand new drug.”
Source: University of Michigan Health System.
Nitroxyl has potential to inhibit breast tumor growth
Latest research from the US has demonstrated that the glycolysis inhibitor, nitroxyl, suppresses the proliferation of breast cancer cell lines grown in vitro and shrinks mammary tumors and their associated blood vasculature in a mouse model of the disease.
As explained by the lead researcher, Mai Brooks, and colleagues from the University of California (LA, USA), non-cancerous cells derive approximately 20–30% of their total energy through glycolysis, whereas cancer cells derive almost their entire daily energy needs from this process. In cancer therapeutics the challenge is, therefore, to inhibit glycolysis without affecting cellular processes in normal cells.
Recent reports suggest that nitroxyl can inhibit the gycolytic enzyme glyceraldehyde 3-phosphate dehydrogenase without affecting the glutathione levels or the oxidation status of cells. Brooks et al. investigated this further by treating two breast cancer cell lines – the highly aggressive estrogen receptor (ER)-negative MDA-MB-231 and the less aggressive ER-positive MCF-7 – with increasing doses of nitroxyl.
Cell proliferation in both lines was suppressed by nitroxyl in a dose-dependent manner, such that a six-fold increase in concentration led to an approximately 3.5-fold reduction in proliferation. Nitroxyl was then injected into the tumors of mice with grafted mammary tumors and tumor xenografts were found to decrease significantly in size, from an average of 1114mm3 to 627mm3 after nitroxyl treatment.
In addition, histologic analysis of slides taken from tumor xenografts revealed that blood vessel density decreased in the tumors of mice treated with nitroxyl relative to control mice not treated with nitroxyl. Explaining their results, the researchers speculate that the effect of nitroxyl is twofold, such that angiogenesis is disrupted while at the same time cellular energy reserves cannot keep pace with tumor growth, resulting in cytostasis and cell death. Brooks et al. state: “So far, our observations do provide intriguing possibilities regarding the cancer therapeutic potential of nitroxyl.”
Source: Norris AJ, Sartippour MR, Lu M et al. Nitroxyl inhibits breast tumor growth and angiogenesis. Int. J. Cancer 122, 1905-1910 (2008).
Genta Incorporated (GNTA) announces licensing agreement for worldwide development of tesetaxel
Drug: Testaxel
Manufacturer: GNTA
Stage of development: Late Phase 2
Genta Incorporated (GNTA) have recently announced that the company has entered into an exclusive worldwide licensing agreement with Daiichi Sankyo Company, Limited (TYO: 4568) for the development and commercialization of tesetaxel (formerly known as DJ-927).
As a late Phase 2 oncology product, tesetaxel has demonstrated anticancer activity in its initial clinical trials, and unlike other taxanes, such as paclitaxel (Taxol(R)) and docetaxel (Taxotere(R); sanofi aventis), the drug has not been associated with severe infusion reactions. Moreover, unlike other oral taxanes that are currently in clinical development, nerve damage has not been a prominent side effect of tesetaxel. Preclinical studies also show that tesetaxel does not share resistance mechanisms that are associated with other taxanes. Thus, the drug offers substantial opportunities to improve patient convenience, safety, and anticancer activity.
“Tesetaxel has demonstrated promising antitumor activity with an acceptable safety profile that offers potential use in a variety of cancer types,” commented Dr Anthony W. Tolcher, Clinical Director of South Texas Accelerated Research Therapeutics (START, TX, USA). “As someone who tested this product and other oral taxanes over the past several years, I am distinctly pleased to see it return to active clinical development.”
More than 250 patients have been treated with oral tesetaxel in Phase I and Phase 2 clinical trials worldwide. The major side effect in clinical trials has been myelosuppression, chiefly neutropenia. Due to the occurrence of severe neutropenia that led to fatal outcomes in several patients with advanced cancer, the drug was placed on clinical hold by the US FDA. Resumption of clinical trials is subject to the lifting of this clinical hold.
“During our extended analysis of this compound, FDA provided clear and specific guidance regarding the tasks that would be required to lift the clinical hold,” commented Dr Raymond P Warrell Jr, Chairman and Chief Executive Officer of Genta. “We believe these tasks are straightforward and we look forward to resuming key clinical trials. We are very pleased to add this important late-stage asset to our pipeline portfolio. Tesetaxel may leverage the considerable anticancer activity of this important drug class with fewer side-effects and improve outcomes for patients.”
Source: www.biocompare.com