Multiple myeloma cell survival relies on high activity of protein kinase CK2

Francesco A. Piazza, Maria Ruzzene, Carmela Gurrieri, Barbara Montini, Luca Bonanni, Gino Chioetto, Giovanni Di Maira, Francesca Barbon, Anna Cabrelle, Renato Zambello, Fausto Adami, Livio Trentin, Lorenzo A. Pinna, and Gianpietro Semenzato

From the Department of Clinical and Experimental Medicine, Hematology-Immunology Division, and the Department of Biological Chemistry, University of Padova School of Medicine, Padova, Italy; and the Venetian Institute of Molecular Medicine, Padova, Italy.

Casein kinase 2 (CK2) is a ubiquitous cellular serine-threonine kinase that regulates relevant biologic processes, many of which are dysregulated in malignant plasma cells. Here we investigated its role in multiple myeloma (MM). Analysis of MM cell lines and highly purified malignant plasma cells in patients with MM revealed higher protein and CK2 activity levels than in controls (normal in vitro-generated polyclonal plasma cells and B lymphocytes). The inhibition of CK2 with specific synthetic compounds or by means of RNA interference caused a cytotoxic effect on MM plasma cells that could not be overcome by IL-6 or IGF-I and that was associated with the activation of extrinsic and intrinsic caspase cascades. CK2 blockage lowered the sensitivity threshold of MM plasma cells to the cytotoxic effect of melphalan. CK2 inhibition also resulted in impaired IL-6-dependent STAT3 activation and in decreased basal and TNF--dependent IB degradation and NF-B-driven transcription. Our data show that CK2 was involved in the pathophysiology of MM, suggesting that it might play a crucial role in controlling survival and sensitivity to chemotherapeutics of malignant plasma cells.

anti–TRAILR1 mAb in multiple myeloma

Mcl-1L cleavage is involved in TRAIL-R1– and TRAIL-R2–mediated apoptosis induced by HGS-ETR1 and HGS-ETR2 human mAbs in myeloma cells

Emmanuelle Menoret, Patricia Gomez-Bougie, Alexandrine Geffroy-Luseau, Sylvanne Daniels, Philippe Moreau, Steven Le Gouill, Jean-Luc Harousseau, Regis Bataille, Martine Amiot, and Catherine Pellat-Deceunynck

From Institut National de la Santé et de la Recherche Médicale (INSERM), Unité 601 (U601), Nantes, France; Université de Nantes, Nantes Atlantique Universités, Nantes, France; Centre Hospitalo-Universitaire (CHU), Service d'Hématologie Clinique, Nantes, France; and Centre de Lutte Contre le Cancer Nantes Atlantique, Saint-Herblain, France.

We evaluated the ability of 2 human mAbs directed against TRAILR1 (HGS-ETR1) and TRAILR2 (HGS-ETR2) to kill human myeloma cells. HGS-ETR1 and HGS-ETR2 mAbs killed 15 and 9 human myeloma cell lines (HMCLs; n = 22), respectively. IL-6, the major survival and growth factor for these HMCLs, did not prevent their killing. Killing induced by either HGS-ETR1 or HGS-ETR2 was correlated with the cleavage of Mcl-1L, a major molecule for myeloma survival. Mcl-1L cleavage and anti-TRAILR HMCL killing were dependent on caspase activation. Kinetic studies showed that Mcl-1L cleavage occurred very early (less than 1 hour) and became drastic once caspase 3 was activated. Our data showed that both the extrinsic (caspase 8, Bid) and the intrinsic (caspase 9) pathways are activated by anti–TRAIL mAb. Finally, we showed that the HGS-ETR1 and, to a lesser extent, the HGS-ETR2 mAbs were able to induce the killing of primary myeloma cells. Of note, HGS-ETR1 mAb was able to induce the death of medullary and extramedullary myeloma cells collected from patients at relapse. Taken together, our data clearly encourage clinical trials of anti–TRAILR1 mAb in multiple myeloma, especially for patients whose disease is in relapse, at the time of drug resistance.

Immunotherapy in multiple myeloma

Optimizing immunotherapy in multiple myeloma: restoring the function of patient's monocyte-derived dendritic cells by inhibiting p38 or activating MEK/ERK MAPK and neutralizing interleukin-6 in the progenitor cells

Siqing Wang, Sungyoul Hong, Jing Yang, Jianfei Qian, Xiang Zhang, Elizabeth Shpall, Larry W Kwak, and Qing Yi^*

University of Texas MD Anderson Cancer Center, Houston, TX, USA

Previous studies demonstrated that circulating dendritic cells (DCs) in myeloma patients were functionally abnormal. However, the phenotype and function of monocyte-derived DCs (MoDCs) from patients, which are commonly used for immunotherapy, were poorly defined. This study was undertaken to examine the quality of MoDCs from myeloma patients compared with cells from healthy donors. We found that patient-derived MoDCs are phenotypically and functionally defective. Compared with their normal counterpart, patient-derived, mature MoDCs expressed significantly lower levels of CD1a, CD40, CD80, and HLA-DR, and were poor at activating alloreactive T cells, presenting recall antigen and activating autologous antigen- and myeloma-specific T cells. These abnormalities may be attributed to elevated production of autocrine cytokines such as IL-6, activated p38 and STAT3, and inhibited MEK/ERK signaling pathways in the progenitor cells. Treatment with neutralizing IL-6-specific antibody and more importantly, p38 inhibitor, or both, could correct these abnormalities. Treating patient-derived cells with these agents not only significantly increased cell yield, but also produced MoDCs that were as functional as their normal counterpart. Thus, this study has delineated the mechanistic defects of MoDCs from myeloma patients, and identified ways for restoring the function of the cells to improve the efficacy of DC-based immunotherapy in this disease.

Thymoglobulin targets multiple plasma cell antigens and has in vitro and in vivo activity in multiple myeloma

Department of Internal Medicine, Division of Hematology, Mayo Clinic, Rochester, MN, USA

Multiple myeloma is characterized by the proliferation of clonal plasma cells that have a heterogeneous expression of various cell surface markers, precluding successful use of monoclonal antibodies for therapeutic targeting of the tumor cell. Thymoglobulin (rabbit-derived polyclonal anti-thymocyte globulin), by virtue of its method of preparation, contains antibodies against several B-cell and plasma cell antigens and offers an attractive option for immunotherapy of myeloma. Here, we demonstrate potent anti-myeloma activity of the rabbit anti-thymocyte globulin preparation Thymoglobulin in vitro and in vivo in an animal model of myeloma. Thymoglobulin was able to induce dose- and time-dependent apoptosis of several myeloma cell lines, including those resistant to conventional anti-myeloma agents. Importantly, the anti-myeloma activity was preserved even when myeloma cells were grown with different cytokines demonstrating the ability to overcome microenvironment-mediated resistance. Thymoglobulin induced apoptosis of freshly isolated primary myeloma cells from patients. Using a competitive flow cytometric analysis, we were able to identify the potential antigen targets for Thymoglobulin preparation. Finally, in a plasmacytoma mouse model of myeloma, Thymoglobulin delayed the tumor growth in a dose-dependent manner providing convincing evidence for continued evaluation of this agent in the clinic in patients with myeloma, either alone or in combination with other agents.

Leukemia advance online publication, 17 August 2006; doi:10.1038/sj.leu.2404359.

PMID: 16932343 [PubMed - as supplied by publisher]

Immunotherapy advance

Researchers from the National Institutes of Health are finding limited but inspiring success in a new approach for fighting cancer, using the immune system to attack the tumors the way it would a cold or flu.

The human immune system doesn't usually fight cancer on its own, so Dr. Steven Rosenberg and his NIH colleagues are trying to genetically engineer it, using a virus they created in the lab that seeks out cancer tumors and attaches to them.

Rosenberg's idea: Mix the cells that seek out the cancer with the immune cells that destroy things and see whether it would create a sort of smart bomb for the cancer.

In the study, Rosenberg tested the approach in 17 patients with advanced melanoma, a dangerous form of skin cancer. All the conventional treatments for the disease already had failed in all of the patients.

In 15 of the patients Rosenberg's engineered immune-cell treatment didn't work, but in two of the patients the cancer seems to have completely disappeared. The findings are published in this week's issue of the journal Science.

The finding has created excitement and hope among cancer experts. Dr. Philip Greenberg of the University of Washington School of Medicine called it "the beginning of a new chapter in treating cancer patients."

First the doctors removed white blood cells called lymphocytes from the patients; the cells are the warriors of the immune system. The lymphocytes were paired with the virus that doctors had genetically engineered in the lab to seek out cancer tumors and attach to them. The hope was that the super-immune cells would destroy the tumors.

Once the immune cells had been genetically engineered, patients underwent chemotherapy to kill most of their original immune cells. Then the new juiced-up cells were infused back into the body and the patients were given a treatment called Interleukin 2, which strengthens the new immune system.

When veterans in the field of cancer, who have had their hopes dashed many times, talk of a study being the beginning of a new chapter in cancer treatment, it draws attention.

The next step for Rosenberg is another clinical trial with potentially stronger gene therapy, and he expects to hear in the next few weeks whether the FDA has approved the trial. He acknowledges that much work lies ahead, but he believes that in the long run this approach will work on about half of all common cancers.

HSP90 KOS-953 is named tanespimycin

Kosan Biosciences Incorporated announced the selection of nonproprietary compound names for its two lead Hsp90 inhibitor compounds. KOS-953 is named tanespimycin and KOS-1022 is named alvespimycin hydrochloride. The compound names have been adopted by the United States Adopted Names Council and the World Health Organization.

Tanespimycin is the most advanced Hsp90 inhibitor in clinical trials. The compound is in a Phase Ib trial in combination with Velcade(R) for multiple myeloma, and is in a Phase I trial as a single agent in multiple myeloma. Kosan's potential registration strategy for tanespimycin is for treatment of multiple myeloma in combination with Velcade in first relapsed patients. In the Phase Ib trial of tanespimycin plus Velcade, some patients who previously failed on Velcade have responded to treatment with the combination, providing another potential treatment option for refractory patients. Kosan could potentially initiate a Phase II/III registrational development program for tanespimycin in the late 2006-early 2007 timeframe. Tanespimycin has been granted orphan drug status in multiple myeloma in the US and in Europe.

Vitamin D and cancer

Vitamin D compounds: clinical development as cancer therapy and prevention agents.

Trump DL, Muindi J, Fakih M, Yu WD, Johnson CS.

Departments of Medicine and Pharmacology, Roswell Park Cancer Institute,

Buffalo, NY 14263, USA. donald.trump@roswellpark.org

Anticancer Res. 2006 Jul-Aug;26(4A):2551-6.

While 1,25 dihydroxycholecalciferol (calcitriol) is best recognized for its effects on bone and mineral metabolism, epidemiological data indicate that low vitamin D levels may play a role in the genesis and progression of breast, lung, colorectal and prostate cancer, as well as malignant lymphoma and melanoma. Calcitriol has strong antiproliferative effects in prostate, breast, colorectal, head/neck and lung cancer, as well as lymphoma, leukemia and myeloma model systems. Antiproliferative effects are seen in vitro and in vivo. The mechanisms of these effects are associated with G0/G1 arrest, induction of apoptosis, differentiation and modulation of growth factor-mediated signaling in tumor cells. In addition to the direct effects on tumor cells, recent data strongly support the hypothesis that the stromal effects of vitamin D analogs (e.g., direct effects on tumor vasculature) are also important in the antiproliferative effects. Antitumor effects are seen in a wide variety of tumor types and there are few data to suggest that vitamin D-based approaches are more effective in any one tumor type. Glucocorticoids potentiate the antitumor effect of calcitriol and decrease calcitriol-induced hypercalcemia. In addition, calcitriol potentiates the antitumor effects of many cytotoxic agents. Preclinical data indicate that maximal antitumor effects are seen with pharmacological doses of calcitriol and that such exposure can be safely achieved in animals using a high dose, intermittent schedule of administration. AUC and C(max) calcitriol concentrations of 32 ng.h/ml and 9.2 ng/ml are associated with striking antitumor effects in a murine squamous cell carcinoma model and there is increasing evidence from clinical trials that such exposures can be safely attained in patients. Another approach to maximizing intra-tumoral exposure to vitamin D analogs is to inhibit their catabolism.

The data clearly indicate that agents which inhibit the major vitamin D catabolizing enzyme, CYP24 (24 hydroxylase), potentiate calcitriol killing of prostate tumor cells in vitro and in vivo. Phase I and II trials of calcitriol, either alone or in combination with carboplatin, taxanes or dexamethasone, as well as the non-specific CYP24 inhibitor, ketoconazole, have been initiated in patients with androgen-dependent and –independent prostate cancer and other advanced cancers. The data indicate that high-dose calcitriol is feasible on an intermittent schedule, no dose-limiting toxicity has been encountered, but the optimal dose and schedule remain to be delineated. Clinical responses have been seen with the combination of high-dose calcitriol + dexamethasone in androgen-independent prostate cancer (AIPC) and, in a large randomized trial in men with AIPC, potentiation of the antitumor effects of docetaxel were seen.

Sticky DNA helps spot leukaemia

US researchers have developed a new technique to distinguish leukaemia cells from healthy ones.

Though cancer cells do not look the same as normal cells, it can be tough for doctors to spot the difference.

A University of Florida team has developed a set of DNA probes which only stick to cancer cells, making it easier to identify them.

The Proceedings of National Academy of Sciences study could lead to improved early diagnosis of cancers.

Leukaemia is the fifth most common cancer in the UK and accounts for about half of all cancers in children. Men are more prone to leukaemia than women.

Cancer cells usually have genetic changes that modify the appearance of the cell.

Nine out of 10 tumour cases are diagnosed by pathologists, looking for these changes under a microscope.

Researchers have recently found that DNA can bind to proteins on the surface of cells.

Using this knowledge, the Florida team designed hundreds of DNA probes labelled with a fluorescent protein.

Following tests, they were able to identify those probes that stuck only to proteins found on the surface of cancer cells.

They were then able to identify the "labelled" cancer cells using a cell-sorting machine more accurately than could be done by the human eye using a microscope.

'Personalised'

The researchers are now trying to develop probes which will only stick to specific types of cancer cell.

This raises the possibility that the probes could be used to give a specific diagnosis of cancer sub-type.

The researchers do not actually know which specific proteins the probe actually binds to.

But they say this is an advantage, because it means that cancer cells can be identified without having to pin down the precise molecular markers which make them different from healthy cells.

Once the technology becomes more sophisticated, however, the researchers believe it could be used to identify slight individual differences among cancer patients - allowing doctors to give more personalised treatment.

Researcher Dr Ying Li said it might also be possible to use the technique to target drug treatments more precisely at cancer cells.

He said: "If we have a marker that can recognise the tumour better than the normal tissue, the marker can be attached with a drug to do target therapy."

Ed Yong, cancer information officer at Cancer Research UK, said: "This is a promising start for what is essentially a completely new method for diagnosing cancer.

"If it proves to be successful in human trials, it could allow doctors to spot tumours much earlier and distinguish between subtly different cancer types.

"As cancers are generally easier to treat when diagnosed early, this could save many lives."

Story from BBC NEWS:
http://news.bbc.co.uk/go/pr/fr/-/2/hi/health/5223382.stm

© BBC MMVI

Roy Scheider fights Multiple Myeloma

Roy Scheider collects the first CancerCare of the Hamptons award from Rudolph Giuliani on Saturday at a charity fundraiser near the actor's house in Sagaponack. Scheider is being honored both for his charity work and for his own battle against multiple myeloma.

Mayo Clinic recommendations for bisphosphonate use in Multiple Myeloma

SCOTTSDALE, Ariz. -- Mayo Clinic's multiple myeloma (MM) research team has jointly issued a consensus statement regarding the use of bisphosphonates to prevent or treat bone disease in MM. Their recommendations address several controversial issues, including the type of bisphosphonate to be used and the duration of such therapy, and are available in the August issue of Mayo Clinic Proceedings.

"It was imperative that we address the issue that has been under recent intense debate due to patient safety concerns," said Martha Lacy, M.D., Mayo Clinic hematologist and lead author of the statement. "These drugs have far-ranging effects that raised concerns in the medical field, so we brought together the relevant specialists to develop a set of best practice recommendations. We published them in Mayo Clinic Proceedings in order to provide other physicians the benefit of our shared knowledge."

The Mayo Clinic team provided recommendations for the myeloma patients for whom bisphosphonates are indicated. They said pamidronate should be the bisphosphonate of choice for patients who are starting therapy, over the newer, more potent drug zoledronic acid, which is more frequently associated with serious damage to jaw bones. Also in the interest of safety, the team recommended that patients without active disease stop bisphosphonate therapy after two years, and patients with active disease reduce the frequency at which the drugs are given.

MM is a malignant plasma cell disorder that is diagnosed in more than 15,000 people each year in the United States, and which causes more than 11,000 deaths. There are a variety of treatment options for MM, but it remains an incurable disease with current emphasis placed on enhancing quality of life while the cure is sought.

Because bone destruction causes significant problems for MM patients, and painful results include osteoporosis, lytic bone disease and skeletal fractures, clinicians seek to treat this condition aggressively. Bisphosphonates are synthetic equivalents of naturally-occurring pyrophosphate, which inhibits bone resorption and aids the body in eliminating excess calcium. These drugs reduce other bony complications related to MM as well.

Unfortunately, along with the positive effects of bisphosphonates comes the possibility of adverse reactions, including kidney function impairment and damage to the jaw bones termed "osteonecrosis of the jaw." "We have tried to balance the undisputed benefits of bisphosphonates with the increasingly well recognized safety concerns," said Vincent Rajkumar, M.D., Mayo Clinic hematologist and co-author. "These recommendations are the result of years of practical knowledge combined by our team into guidelines for use beyond our institution. We hope others will adopt them as well as continue researching other solutions."

This consensus statement was a multidisciplinary effort, in which the myeloma group worked closely with periodontists and oral/maxillofacial surgeons to assess risks and benefits. Besides Drs. Lacy and Rajkumar, the team included researchers from Mayo Clinic's three campuses in Arizona, Florida and Minnesota, including: Lief Bergsagel, M.D.; Alan Carr, D.M.D.; Robert Dalton, M.D.; David Dingli, M.D., Ph.D.; Angela Dispenzieri, M.D.; Rafael Fonseca, M.D.; Morie Gertz, M.D.; Kimberly Gollbach; Philip Greipp, M.D.; Suzanne Hayman, M.D.; Deepak Kademani, D.M.D., M.D.; Eugene Keller, D.D.S.; Shaji Kumar, M.D.; Robert Kyle, M.D.; John Lust, M.D., Ph.D.; Craig Reeder, M.D.; Vivek Roy, M.D.; Stephen Russell, M.D., Ph.D.; Keith Stewart; Christopher Viozzi, D.D.S., M.D.; Thomas Witzig, M.D.; and Steven Zeldenrust, M.D., Ph.D.

Mayo Clinic is the first and largest integrated, not-for-profit group practice in the world. As a leading academic medical center in the Southwest, Mayo Clinic focuses on providing specialty and surgical care in more than 65 disciplines at its outpatient facility in north Scottsdale and at Mayo Clinic Hospital.

Source: http://www.mayoclinic.org/news2006-sct/3586.html

Osteonecrosis of the Jaw update for Multiple Myeloma

Incidence, risk factors and management of osteonecrosis of the jaw in patients with multiple myeloma: a single-centre experience in 303 patients.

Zervas K, Verrou E, Teleioudis Z, Vahtsevanos K, Banti A, Mihou D, Krikelis D, Terpos E.

Department of Haematology/Oncology, "Theagenion" Cancer Center, Thessaloniki, Greece.

The incidence, characteristics and risk factors for the development of osteonecrosis of the jaw (ONJ) were evaluated among 303 myeloma patients. Only patients who received bisphosphonates developed ONJ (28/254; 11%). Zoledronic acid produced 9.5-fold greater risk for developing ONJ than pamidronate alone (P = 0.042) and 4.5-fold greater risk than subsequent use of pamidronate + zoledronic acid (P = 0.018). Use of thalidomide and number of bisphosphonate infusions also increased the risk for ONJ by 2.4-fold (P = 0.043), and 4.9-fold respectively (P = 0.012). ONJ developed earlier among patients receiving zoledronic acid. Our data indicates that administration of zoledronic acid for more than 2 years or in combination with thalidomide requires caution in myeloma.

PMID: 16889620 [PubMed - as supplied by publisher]

Current status of RIC Allo SCT for Multiple Myeloma

The current status of reduced-intensity allogeneic hematopoietic stem cell transplantation for multiple myeloma.

Bensinger WI.

Fred Hutchinson Cancer Research Center, University of Washington, Seattle, WA, USA.

Of all the treatment modalities employed to control multiple myeloma, only allogeneic hematopoetic stem cell transplantation is potentially curative, due in large part to a graft-versus-myeloma (GVM) effect.

Whereas patients who receive either allogeneic or autologous stem cell transplants for multiple myeloma have similar 3-5-year survival, only allograft recipients appear to enjoy long-term disease-free survival. High transplant-related mortality (TRM) associated with allogeneic stem cell transplantation is currently the major limitation to wider use of this potentially curative modality. This high mortality has been the major impetus for exploration of reduced intensity conditioning (RIC) regimens designed to allow engraftment of allogeneic stem cells. With follow-up now extending to 7 years, it is clear that when compared to myeloablative transplants, RIC allografts are associated with lower TRM; however, reduced mortality comes at a cost of higher rates of disease progression and relapse. Strategies designed to improve the therapeutic index of allografts include the use of more intensive, yet still non-myeloablative conditioning regimens, tandem autologous plus RIC allografts, peripheral blood cells rather than bone marrow, graft engineering to improve the GVM activity while reducing graft-versus-host disease, post-transplant maintenance and targeted conditioning therapies such as bone-seeking radioisotopes. Leukemia advance online publication, 3 August 2006; doi:10.1038/sj.leu.2404333.

PMID: 16888617 [PubMed - as supplied by publisher]

Environmental chemicals and multiple myeloma

Studies in cancer causation have often concluded that exposure to carcinogenic or endocrine-disrupting chemicals, for example, organochlorines (OC) – found in pesticides and plastics – occurs at concentrations that are too low to be considered a major factor in cancerous disease.

New research at the University of Liverpool, published in the Journal of Nutritional and Environmental Medicine, has found that exposure even to small amounts of these chemicals may result in an increased risk of developing cancer.

The research consisted of systematic reviewing of recent studies and literature concerning the environment and cancer. Professor Vyvyan Howard and John Newby, also found that genetic variations, which can predispose some people to cancer, may interact with environmental contaminants and produce an enhanced effect.

Howard said: “Organochlorines are persistent organic pollutants (POPs), which disperse over long distances and bioaccumulate in the food chain. For humans the main source of OC exposure is from diet, primarily through meat and dairy products.

The research team has also looked at anecdotal evidence, from practicing physicians in pre-industrial societies, which suggests that cancerous disease was rare among particular communities, such as the Canadian Inuits and Brazilian Indians. This suggests that cancer is a disease of industrialisation.

Howard concluded: “The World Health Organisation estimates that between one and five per cent of malignant disease in developed countries is attributed to environmental factors; but our research suggests this figure may have been underestimated.”

The researchers also point out: the incidence of cancer in the UK has risen between 1971 and 1999; non-Hodgkin’s lymphoma has risen by 196 per cent in men and 214 per cent in women; prostate cancer and testicular cancer have risen by increased by 152 per cent and 139 per cent respectively; breast cancer has risen by 75 per cent and multiple myeloma by 100 per cent and 86 per cent in men and women respectively.

Jamie Page, chairman of Cancer Prevention and Education said: “This research is very important and suggests that there are links between chemicals and cancer. It is our opinion that if progress if to be made in the fight against cancer, far more attention and effort must be made to reduce human exposure to harmful chemicals.”

As the Liverpool scientists were publishing their findings, the European Commission was busy adopting new legislation setting maximum levels for the sum of dioxins and dioxin-like polychlorinated biphenyls (PCBs) in food and feed.

Maximum levels for dioxins in food of animal origin and all animal feed have been applicable since July 2002. However, due to lack of sufficient data and scientific information at the time, no levels were set for dioxin-like PCBs.

Since 2002, new data on dioxin-like PCBs has become available, and the new legislation lays down mandatory limits for the combined level of dioxins and dioxin-like PCBs.

From November 2006, any food or feed in which the sum of dioxins and dioxin-like PCBs exceeds these maximum levels will not be allowed to be marketed in the EU.

The reduction of persistent chemicals such as dioxins and dioxin-like PCBs in the food chain is an important part of ensuring the health and safety of EU consumers.

New drug PD 0332991

A team of researchers at Weill Medical College, Cornell University in New York City report an experimental drug targeted to a cancer-causing mechanism within the cell may be a powerful weapon against multiple myeloma.

PD 0332991 is an orally active, small molecule which inhibits specific enzymes and proteins that dysregulate the cell's division and expansion.

"Previous work in our lab showed that when these kinase enzymes -- Cdk4 or Cdk6 -- inappropriately match up with regulatory proteins called cyclin D1 or D2, you get the uncontrolled proliferation of cells that is a hallmark of myeloma relapse," explains senior researcher Dr. Selina Chen-Kiang of Weill Cornell Medical College. That research was published in December, 2005 in Cancer Research.

Either combination -- Cdk4/cyclin D1 or Cdk6/cyclin D2 -- is like "adding gas to an engine," she explains. "Now, what we've found is a pharmacologic ‘brake' that stops the myeloma motor, cold."

Because these enzyme-cyclin pairings can help trigger the proliferation of cancer cells in general, inhibitors like PD 0332991 might prove useful in treating a wide range of tumors.

"There are drugs that are geared to getting people into remission, but they ultimately fail because there are still cancer cells that have the potential for self-renewal -- they'll rise again and start dividing," Dr. Chen-Kiang explains.

Her lab's discovery last year of just how relapse occurs was a real breakthrough. The "sequel," Dr. Chen-Kiang says, was to find an agent that could stop it.

"We knew what we were looking for: a pill whose active agent was a molecule small enough that it could get deep inside the myeloma cell," adds co-lead researcher Dr. Maurizio Di Liberto, assistant research professor of pathology and laboratory medicine at Weill Cornell. "The drug also had to be highly targeted -- it had to stop the proliferation of myeloma cells without harming normal cells," he said. Researchers at the drug giant Pfizer, Inc., had already been busy developing just such an agent -- PD 0332991.

PD 0332991 effectively prevented the growth of myeloma tumors in mice. The drug appeared to inhibit Cdk4 and Cdk6 in a way that was proportional to the proliferating state of the cell. The greater the combined negative effect of Cdk4 and Cdk6, the more PD 0332991 inhibited it.

"We noted that PD 0332991, by itself, does not induce apoptosis -- the death of existing cancer cells," Dr. Chen-Kiang explains. "So we wondered if combining it with other agents might help."

The team coupled PD 0332991 with dexamethasone, a drug commonly used against multiple myeloma.

"Using these two drugs together seemed to have a synergistic effect. We observed markedly enhanced killing of myeloma cells, even though we used one-tenth the dose of dexamethasone that's usually delivered to patients," Dr. Chen-Kiang reports.

The researchers are hopeful that combining PD 0332991 with other chemotherapies will be equally or more effective. Early data suggest that this approach will bring equally impressive results.

The advent of a mechanism-specific agent that stops multiple myeloma in its tracks is both unique and exciting, the research team says.

"It's controlling the disease by controlling the mechanism of myeloma cells' division," Dr. Baughn explains. "We've never had anything like this before."

"Scientists have known for a long time that Cdk4 and Cdk6 play key roles in the proliferation of nearly all cancer cell types, but until now we haven't found an agent that specifically targets only those two enzymes," she says.

"We're confident that if this works in myeloma, it should work in a wide range of other tumors, too," she says.

This study was funded by grants from the National Institutes of Health and the Leukemia and Lymphoma Society.

See also http://myelomic.blogspot.com/2005/12/weill-cornell-team-identifies-trigger.html