Drugs known as HDAC inhibitors, which have antitumor activity and can be used to treat some forms of skin cancer and some types of leukemia, are also known to have anti-inflammatory properties, but the mechanisms by which they modulate the immune system have not been determined.  New data, generated by Pavan Reddy and colleagues, at the University of Michigan Cancer Center, Ann Arbor, have now indicated one mechanism by which HDAC inhibitors modulate the mouse and human immune system and the information gained has been used to develop an approach to protect mice from graft-versus-host disease after bone marrow transplantation.

In the study, two different HDAC inhibitors were shown to prevent mouse and human immune cells known as dendritic cells (DCs) from initiating proinflammatory immune responses in vitro.  Further, if Dcs treated ex vivo with HDAC inhibitors were injected into mice after they had received a bone marrow transplant, the incidence and severity of graft-versus-host disease was dramatically reduced.  Detailed analysis revealed that the HDAC inhibitors mediated their effects by inducing Dcs to express more of a molecule known as IDO, which is a suppressor of DC function.  The authors therefore hope that their data provide support for studies to determine whether HDAC inhibitors might be of benefit to individuals receiving bone marrow transplants and to those with other immune-mediated diseases.

Drugs that target members of the EGFR family of proteins have proven effective for the treatment of certain types of cancer, including breast cancer.  However, in a large number of patients for whom the treatment initially works well, the tumor recurs and is resistant to the effects of the drug.  New insight into the mechanisms of tumor resistance to a drug known as gefitinib, which targets EGFR, has now been provided by a team of researchers at Vanderbilt University Medical Center, Nashville, and Massachusetts General Hospital Cancer Center, Charlestown.  As discussed by both the authors and, in an accompanying commentary, Mark Greene and Qiang Wang, at the University of Pennsylvania Medical Center, Philadelphia, these observations help us understand why tumors become resistant to the effects of EGFR-targeted drugs, information that is essential if more effective therapies are to be developed.

The team, led by Carlos Arteaga and Jeffrey Engelman, generated cancer cells resistant to the effects of gefitinib and found that these cells were constantly sending signals from a protein on their surface known as IGF1R.  This meant that two proteins known as IRS-1 and PI3K were always associated.  If this association was disrupted then the cells once again became susceptible to the effects of gefitinib.  Further analysis showed that if mice with a human tumor were treated with gefitinib and a drug inhibiting IGF1R their tumors did not recur, whereas neither drug alone could prevent tumor recurrence.  The authors therefore suggest that drug combinations that target both EGFR and IGF1R might be of benefit to individuals with cancers that are responsive to EGFR-targeted therapies.

The development of resistance to anticancer chemotherapeutic agents remains a large problem. In some cases, such resistance is associated with altered control of a cellular process known as translation, which is central to the generation of proteins. New data, generated by Jerry Pelletier and colleagues, at McGill University, Montreal, have identified a drug that can enhance the sensitivity of mouse cancer cells to standard anticancer chemotherapeutic agents.

In the study, small molecules were screened for their ability to inhibit the initiation of translation by modifying the function of a protein known as eIF4A, which has a central role in translation initiation. A class of natural drugs known as cyclopenta[b]benzofuran flavaglines were found to have the desired effects and one member of this class of compounds was shown to reverse the resistance of cancer cells to anticancer chemotherapeutic agents in a mouse model of lymphoma. The authors therefore suggest that developing approaches to inhibit translation initiation by targeting eIF4A might provide a way to altering drug resistance in cancers exhibiting altered control of translation initiation.

A novel type of drug can shrink primary breast cancer tumors significantly in just 6 weeks Research provides leads to a new target in cancer treatment -the cancer stem cell.

(Berlin, Germany) A drug that targets the cell surface receptors that play an important role in many types of cancer can bring about significant tumour regression in breast cancer after only six weeks of use, a scientist told the 6th European Breast Cancer Conference (EBCC-6) today (Thursday 17 April).  Dr. Angel Rodriguez, from the Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, USA, said that the work demonstrated for the first time that the tyrosine kinase inhibitor lapatinib could decrease tumour-causing breast cancer stem cells in the primary breast cancers of women receiving neoadjuvant treatment (treatment given before the primary surgery for the disease).

Dr. Rodriguez and colleagues studied 45 patients with locally advanced breast cancer in which the gene HER-2 was over-expressed.  The patients received lapatinib for six weeks, followed by a combination of weekly trastuzumab and three-weekly docetaxel, given over 12 weeks, before primary surgery.  Biopsies were performed at the time of diagnosis and also after six weeks of lapatinib and cells from the tumours were obtained and analyzed.

“We saw significant tumour regression after six weeks of single agent lapatinib,” said Dr. Rodriguez.  “Bi-dimensional tumour measurements showed a median decrease of minus 60.8%. We had previously showed that tumour-causing breast cancer stem cells were resistant to conventional preoperative chemotherapy; indeed, residual cancers that were exposed to such chemotherapy showed an increase in tumour-causing cells and enhanced tumour initiation by the formation of mammospheres, small tumours that form when tumour-causing cells are cultured in a test tube, which reflect the capacity of the cells to self-renew.  So we were excited to see that the results with lapatinib were different.”

Dr. Rodriguez’s results suggest that specific signalling inhibitors of the pathways responsible for stem cell self-renewal could provide a possible therapy for eliminating tumour-causing cells in order to achieve the long-term eradication of cancer.

Cancer stem cells help maintain the malignant tissue in the tumour by regenerating the tumour after attack from chemotherapy drugs.  “This indicates that the stem cells themselves should be the specific target of chemotherapy drugs,” said Dr: Rodriguez.  “Rather than the broad brush approach, in which cells are killed indiscriminately, targeting the stem cells may be more effective and also prevent some of the unpleasant side effects associated with conventional chemotherapy treatment.”

Scientists believe that cancer stem cells come into being through damage to their own DNA, which affects the regulation of their self-renewal.  Other cells divide into two ‘daughter’ cells, but a stem cell can divide into a new stem cell and a ‘progenitor’ cell.  The progenitor cell loses the power of self-renewal, but can still change into the cell type of the tissue served by the stem cell.  The stem cell population then continues to renew itself as it generates new cells for the tissue.  “This means that, unlike other cells, the stem cell has lost control over its own population size,” said Dr. Rodriguez.

Lapatinib has few side effects, and those that exist are minimal, including diarrhoea and acne.  But it is expensive.  “In the US it costs between $2000 and $3000 a month,” he said.

“This is an exciting finding, and we will be starting further studies on stem cells in order to confirm it.  We will also look into its applicability in testing novel agents targeting tumour-initiating cells.  This finding should also apply to other types of cancers and research of tumour-initiating stem cells in other cancers is ongoing,” said Dr. Rodriguez.

“International studies are currently underway looking at the effect of lapatinib in lung, colon, head and neck, gastric, oesophageal, and bladder cancer and lymphoma, among others,” he said.

Note:  Lapatinib has not yet been licensed for use in the EU, although it has been approved in Switzerland and received a positive opinion regarding a conditional marketing authorisation from the European Medicines Agency in December.  This conditional authorisation refers to its use in patients with advanced or metastatic breast cancer with HER-2 over-expression in the tumours.

Catalogue no: 204, Thursday 18 April, 17.15 hrs CEST (Hall 1)

A new drug compound leads to the death of ovarian cancer cells resistant to chemotherapy.

Dr. Gil Mor, Associate Professor in the Department of Obstetrics, Gynecology & Reproductive Sciences at Yale School of Medicine.

Credit: Yale University

In a discovery that may be useful for maintaining remission in chemo-resistant ovarian cancer, Yale scientists report that pre-clinical studies have shown the drug compound NV-128 can induce the death of ovarian cancer cells by halting the activation of a protein pathway called mTOR.

Gil Mor, M.D., associate professor in the Department of Obstetrics, Gynecology & Reproductive Sciences at Yale School of Medicine, and associate research scientist Ayesha Alvero, M.D. presented the data April 15 during an oral presentation at the annual meeting of the American Association for Cancer Research.

In cancer cells, mTOR signals enhance tumor growth and may be associated with resistance to conventional therapies.  Inhibition of mTOR could shut down many of these survival pathways, including proteins that protect the mitochondria of cancer cells.

NV-128, developed by Novogen Limited, holds promise as a more targeted therapy for ovarian cancer because it works differently from traditional therapies that are dependent on enzymes known as caspases to trigger cell death.  Therapies using caspases to kill cancer cells can be ineffective in chemo-resistant cancer cells due to mutations that short-circuit signals that trigger cancer cell death.

“We consider that the capacity of NV-128 to trigger caspase-independent cell death, in otherwise chemoresistant ovarian cancer cells, opens new possibilities for the use of NV-128 as a potential addition to conventional chemotherapy targeting ovarian cancer cells,” said Mor.

In the context of developing therapies for late stage ovarian cancer, Mor said, the finding may be “a key step to the development of alternative targeted therapy for patients with cancer recurrence.”