186-Gene Signature in Cancer Stem Cells Predicts Recurrence

tanford University School of Medicine researchers found 186 genes that together can predict the risk of recurrence in breast cancer patients. These genes identified in cancer stem cells found inside a tumor also predict the recurrence of prostate cancer, lung cancer and medulloblastoma.

	“These data suggest that there are some fundamental properties of the malignancy that are shared between many types of tumors,” explained Michael Clarke, MD, the Karel H. and Avice N. Beekhuis professor in cancer biology. Dr. Clarke is also the lead author of the study, which is published in the January 18 issue of the 

	Dr. Clarke also found that coupling this 186-gene signature with a second group of genes implicated in normal cells  surrounding the tumor, called stromal cells, one can predict aggressive cancers with an even greater accuracy. Patrick Brown, PhD, professor of biochemistry, previously discovered these genes. Dr. Clarke said the finding shows that malignancy is the result of an interaction between the cancer cells in the tumor and the environment, as many researchers had previously surmised.

	Dr. Clarke and his team identified the genetic pattern in breast cancer stem cells taken from tumors and verified the results in a standard tumor biopsy containing a range of cell types. That same biopsy can also remove the stromal cells that are needed for the second genetic profile.

	“This paper demonstrates, for the first time, the clinical value of isolating pure human cancer stem cells,” pointed out Irving Weissman, MD, director of the Stanford Institute for Stem Cell Biology and Medicine, who was not involved in the study. “Mike Clarke and his colleagues have now shown that the human breast cancer stem cell reveals information not evident when the whole tumor is analyzed. We plan to incorporate these findings in our approaches to the care of cancer patients, starting here at Stanford.”

	Dr. Clarke has begun working with surgeons on tools to assess the best treatment for each patient. For example, he hopes that within five years, if a patient’s genetic profile implies that her tumor is unlikely to return, a surgeon will be able to leave more breast tissue intact.

	Over time, Dr. Clarke said, researchers will likely be able to refine the list of genes needed to most accurately determine a patient’s risk of recurrence. Such a shorter list of genes could make a genetic profiling test more cost-effective for widespread use.

	Clarke found the first cancer stem cell in a solid tumor in 2003 while at the University of Michigan. Previously, researchers thought these cells were restricted to blood cancers. Since then, other researchers have found them in brain, prostate as well as head and neck cancers.

	Other Stanford researchers who contributed to this study include Piero Dalerba, MD, postdoctoral scholar, and Gavin Sherlock, PhD, assistant professor of genetics. This work was supported by grants from the National Cancer Institute, the Breast Cancer Research Foundation and the Virginia and D.K. Ludwig Foundation.

                                                                                                                                                                                                —Querida Anderson

National Prostate Cancer Coalition Commences Clinical Trial Education Program

	The National Prostate Cancer Coalition (NPCC) launched a program to educate men with prostate cancer about the possibility of entering relevant clinical trials. “We’re conducting our “Get in the G.A.M.E. -Get All Men Educated” initiative because a recent survey of prostate cancer patients shows that only a very small percentage of patients—about 12 percent of men with prostate cancer&mdash;know that clinical trials are an option,” explained Richard N. Atkins, MD, NPCC CEO.

	The program supports the notion that prostate cancer clinical trials are not only integral to the drug discovery and development process but also provide access to potential new therapies. “Clinical trials examine the safety and benefit of experimental drugs to find new treatments for prostate cancer aimed at extending and improving quality of lifeand ultimately a cure,” adds Dr. Atkins. “It’s important for men to ask their urologist or oncologist about trials that may be helpful.”

	In particular, discussing with one’s doctor about clinical trials is important for men with recurrent disease who are at risk for or already suffering from bone metastases, according to the NPCC. “Being informed of clinical trials is particularly important for men with recurring prostate cancer for whom fewer approved therapies exist,” said Atkins.  “In fact, certain cancers are more likely to spread to the bone than others and prostate cancer is one of them.”

	The NPCC initiatives comes after the FDA, in June 2006, announced a series of new policy and regulatory developments—The Human Subject Protection and Bioresearch Monitoring (HSP/BIMO) Initiative&mdash;to strengthen the Agency’s ability to protect patients in clinical trials and monitor them to ensure integrity of resulting data.

	The study, “Cancer Clinical Trials Awareness and Attitudes in Cancer Survivors,” conducted by the Coalition of Cancer Cooperative Groups and Northwestern University, surveyed nearly 2,000 U.S. cancer survivors. It determined that as few as one in 10 cancer survivors were given the option of being part of a trial during treatment. Among those patients who did participate in clinical trials, the survey found that 92% had a positive experience.

	“This survey tells us that we need to do a better job of informing men about clinical trials that may make a difference in how their disease is managed in helping determine the potential benefit of new agents,” said Matthew Smith, MD, PhD, assistant physician, division of hematology/oncology, Massachusetts General Hospital, Boston. “We are currently conducting clinical trials to evaluate the potential for an investigational therapy to prevent and treat the bone metastases in men with prostate cancer.”

Concomitant High-Dose Radiation Therapy Plus Cetuximab Improves Locoregional Control and Reduces Mortality, with No Increase in Radiation Therapy—Associated Toxicity in Patients with Advanced Squamous-Cell Carcinoma of the Head and Neck

adiation therapy is the standard treatment for patients with advanced, unresectable squamous-cell carcinoma of the head  and neck. Unfortunately, however, the results of treatment are poor and radiation therapy—associated toxicity is a common problem. In a recent study published in the

, patients with locally advanced squamous-cell carcinoma of the head and neck who were treated with cetuximab (a monoclonal antibody against epidermal growth factor  receptor) in addition to radiation therapy showed a survival benefit, with no increase in mucositis or dysphagia compared with patients who received radiation therapy alone.

	The study, performed by Bonner and colleagues, was a multinational, randomized study performed to compare radiation  therapy alone with radiation therapy plus cetuximab. Patients (n=424) were randomly assigned to treatment with either  high-dose radiation therapy alone (n=213) or high-dose radiation therapy plus weekly cetuximab (n=211) at an initial dose of 400 mg/m

 weekly for the duration of radiation therapy. The primary endpoint was the duration of control of locoregional disease; secondary end points included overall survival, progression-free survival, response rate, and safety.

	The median duration of locoregional control was 24.4 months among patients treated with cetuximab plus radiation therapy, compared with 14.9 months among those given radiation therapy alone (

 = 0.005). The median follow-up period was 54.0 months. The median duration of overall survival was 49.0 months among patients treated with combined therapy, compared with 29.3 months among those treated with radiation therapy alone (

 = 0.03). Radiation therapy plus cetuximab significantly prolonged progression-free survival (

 = 0.006). With the exception of skin rash and infusion reactions, the incidence of grade 3

	or greater toxic effects, including mucositis, did not differ significantly between the two groups.

	The investigators concluded that treatment of locoregionally advanced head and neck cancer with concomitant high-dose radiation therapy plus cetuximab improves locoregional control and reduces mortality without increasing the common toxic effects associated with radiation therapy to the head and neck. According to Dr. Bonner, lead author of the study and a radiation oncologist at the University of Alabama in Birmingham, AL, “These findings are important because they show that the addition

	of this monoclonal antibody therapy has lifesaving benefits without any additional length of suffering from the primary acute  side effects.”

STAT3 Pathway Inhibitor (Degrasyn) Drug Class Shows Promise in the Treatment of

espite improvements in surgical techniques, neuroimaging, radiation therapy, and chemotherapy, high-grade gliomas are notoriously difficult to cure, and prognosis is often abysmal. Numerous medical centers worldwide are involved in basic research in an effort to more fully elucidate the basic mechanisms of brain tumor growth and in the development of novel therapies. These efforts have led investigators to inhibitors of signal transducer and activator of transcription-3 (STAT3) phosphorylation.

	Previous investigations have shown that AG490, a selective inhibitor of STAT3 phosphorylation, inhibits growth and induces

	apoptosis in some cancer cell types. However, although AG490 routinely shows in vitro anticancer activity, it has not consistently

 antitumor effect in animal models. This observation led Iwamaru and colleagues to evaluate WP1066, a novel inhibitor structurally related to AG490 but significantly more active and potent against human malignant glioma U87-MG and U373-MG cells in vitro and in vivo. Their findings were published recently in 

	The results were striking. The IC50 values for WP1066 were 5.6 μM in U87-MG cells and 3.7 μM in U373-MG cells, which  represents 18- and 8-fold increases in potency, respectively, over that of AG490. WP1066 activated Bax, suppressed the expression of 

, and induced apoptosis. Systemic intraperitoneal administration of WP1066 in mice significantly (

 < 0.001) inhibited the growth of subcutaneous malignant glioma xenografts during the 30-day follow-up period. Immunohistochemical analysis of the surgically removed tumors showed that phosphorylated STAT3 levels in the WP1066 treatment group remained inhibited at 3 weeks after the final WP1066 injection, whereas tumors from the control group expressed high levels of phosphorylated STAT3. The investigators concluded that WP1066 may holds promise as a therapeutic

	STAT3 is activated constitutively in a variety of cancer types, including malignant gliomas. STAT3 is activated by phosphorylation of a tyrosine residue, after which it dimerizes and translocates into the nucleus. In the nucleus, it regulates the expression of several genes responsible for proliferation and survival at the transcriptional level. STAT3 pathway inhibitors (degrasyns) are a new class of drugs that were discovered by Prof. Waldemar Priebe and colleagues at The University of Texas MD Anderson Cancer Center and licensed to Callisto Pharmaceuticals in January 2006. The unique antitumor activity of STAT3 pathway inhibitors relates to their ability to selectively promote degradation of key proteins that are involved in tumor cell proliferation and survival. This degradation appears to be specific for 

, all important targets for a wide range of  tumors. Callisto has sponsored-research agreements in place with the MD Anderson Cancer Center, which seek to identify and develop clinical candidates from this new and interesting class.

Articles

News items reported in this issue:  1) 186-Gene Signature in Cancer Stem Cells Predicts Recurrence 2) National Prostate Cancer Coalition Commences Clinical Trial Education Program 3) Concomitant High-Dose Radiation Therapy Plus Cetuximab Improves Locoregional Control and Reduces Mortality, with No Increase in Radiation Therapy%u2013Associated Toxicity in Patients with Advanced Squamous-Cell Carcinoma of the Head and Neck, and more

News Reports; March 2007

%u25BA AVAX and CTCA Collaborating for Cancer Therapies

VAX Technologies, Inc., a developer of therapeutic cancer vaccines located in Philadelphia, PA, and Cancer Treatment Centers of America, Inc. (CTCA), a network of cancer treatment hospitals and facilities, are collaborating for the benefit of both parties’ cancer therapeutic products. The agreement will advance AVAX’s OVax ovarian cancer vaccine by facilitating a study at CTCA’s centers. At the same time, AVAX will produce CTCA’s activated natural killer cell technology for the treatment of various cancers.

	The terms of the collaboration are for a three-year period, during which CTCA will provide AVAX with a funding of $1.15 billion for research and development. CTCA will fund the initial production of vaccines, and for AVAX’s clean room facility, where the company will produce its vaccines as well as CTCA’s natural killer cell preparations.

	AVAX plans to activate a phase I/II IND for the treatment of stage III and IV ovarian cancer patients who have relapsed after chemotherapy. The study will evaluate patients for safety and immunological responses. It will be based at CTCA’s hospital in Zion, IL, where CTCA expects to start treating patients this summer.

	The new O-Vax vaccine looks promising because it is based on the same technology as AVAX’s metastatic melanoma vaccine M-Vax, which has already been launched commercially in Switzerland and has the US FDA’s orphan drug designation. The technology, called haptenization, works by attaching a chemical hapten to tumor antigens, making it easier for the immune system to recognize the tumors. The safety and efficacy of M-Vax has been evaluated in more than 400 patients with stage III and IV melanoma, and the vaccine has been shown to increase five-year overall survival in patients with stage III melanoma. The newer O-Vax product has also seen good news recently—two phase I/II trials for the O-Vax product have provided  encouraging results showing that the vaccine may prove effective in chemotherapy-resistant ovarian cancer.

	“To win the fight against cancer, it is absolutely vital we do everything we can to make innovative new treatments like this available to patients as soon as possible,” said Edgar Staren, chief medical officer of CTCA. “It’s inconceivable that treatments like these that  give hope to patients are often lefton the laboratory bench, while cancer patients are told there is nothing more that can be done for them.”

                                                                                                                                                                                              —Prachi Petal-Predd

%u25BA Full Speed Ahead for GPC Biotech's Satraplatin

fter recently announcing positive results from a phase III registrational trial evaluating satraplatin against hormone refractory prostate cancer, biopharmaceutical company GPC Biotech AG has launched an expanded access program for the drug. The results of the trial showed that satraplatin significantly reduces the risk of disease progression in patients.

	GPC Biotech, which is headquartered in Frankfurt, Germany, is expecting overall survival data later this year, but the company is moving forward with marketing approval applications. It has already filed the New Drug Application for satraplatin with the US FDA and expects to file an application in the EU by the end of the second quarter.

	“Moving forward, we plan to work closely with the FDA regarding our application for marketing approval of satraplatin in the US,” said Bernd R. Seizinger, MD, PhD, chief  executive officer of GPC Biotech. “We also are continuing to aggressively build our marketing and sales organization in the US to prepare for a potential launch of satraplatin later this year.”

	The company announced the results of the Satraplatin and Prednisone Against Refractory Cancer (SPARC) trial at the American Society of Clinical Oncology Prostate Cancer Symposium in September 2006. The trial compared the effectiveness of  satraplatin plus prednisone and placebo plus prednisone in 950 patients with refractory cancer who have failed chemotherapy treatment. Final progression-free survival (PFS) results for the SPARC results were presented by Daniel Petrylak, MD, associate professor of medicine at Columbia University College of Physicians & Surgeons, director of the Genitourinary Oncology  Program at New York-Presbyterian Hospital/Columbia, and a principal investigator in the SPARC Study on February 24 at the American  Society of Clinical Oncology (ASCO) Prostate Cancer Symposium in Orlando, Florida. Two different designs of the study showed a relative risk reduction in disease progression of 40% and 33% respectively. These results were consistent irrespective of the chemotherapy that the patients had already received.

	According to Dr. Petrylak: “As there are currently no approved therapies for patients with hormone-refractory prostate cancer whose disease has already failed on one chemotherapy regimen, satraplatin has the potential to address a mounting area of unmet medical need. The data I am presenting show statistically significant results in progression-free survival in favor of those patients treated with satraplatin. These results are consistent no matter what the prior chemotherapy treatment, including Taxotere® [docetaxel, Sanofi-Aventis].”

	Under GPC Biotech’s newly launched expanded access program, patients whose first-line chemotherapy has failed will have access to satraplatin free of charge from clinicians’ offices. Unlike other platinum compounds, which need to be administered intravenously, satraplatin comes in the form of capsules that patients can take at home.

                                                                                                                      — Parts of this story were contributed by John D. Zoidis, MD

%u25BA Collaboration for New Oncology Compounds

ristol-Myers Squibb Company and Adnexus Therapeutics have announced a partnership to discover and develop Adnectin-based biological compounds for oncology-related targets. Waltham, MA-based Adnexus is the sole developer of Adnectins, a class of therapeutic proteins derived from human fibronectin that are designed and optimized using the company’s PROfusion protein design engine.

	Under the agreement terms, Adnexus will identify and deliver pre-clinical Adnectin candidates to Bristol-Myers Squibb, which will then focus on global development and commercialization. Adnexus will retain a limited co-promotion right to the first product that is approved in the US.

	Bristol-Myers Squibb will provide approximately $30 million over the next three years to Adnexus. These funds will consist of upfront and guaranteed research payments.

	In addition, Adnexus is eligible to receive regulatory milestone payments of up to $210 million per product, as well as royalties on product sales and sales-based milestone payments.

                                                                                                                                                                                           —Prachi Petal-Predd

%u25BA Graffinity and Amgen in Drug Discovery Ageement

raffinity Pharmaceuticals GmbH, a developer of fragment-based drug discovery technology headquartered in Heidelberg, Germany, announced a drug discovery research agreement with Amgen on February 25. As per the agreement, Graffinity will get technology access fees and success payments for generating small molecule hits against a broad range of drug targets. According to the company, it offers one of the largest fragment libraries commercially available today—about 20,000 fragments and 90,000 lead-like structures.

	Thousand Oaks, CA-based Amgen will gain access to Graffinity’s fragment-based drug discovery technology. The technology uses microarrays to screen for molecule fragments that bind to a variety of drug targets that are already available or about to be discovered by genomics, which would help in fighting many major human diseases, including cancer.

	The major focus of the collaboration is chemistry research and the identification of novel modes of action. The companies did not disclose the financial details of the transaction.

                                                                                                                                                                                             —Prachi Petal-Predd

%u25BA Roche Suspends Enrollment in CERA Phase II Oncology Trial

n February 23, Roche announced that it is temporarily suspending recruitment into its phase II dose-finding study (NH19960) with the investigational drug CERA (Continuous Erythropoiesis Receptor Activator) in anemic patients with advanced (stage IIIB or IV) non—small-cell lung cancer who are receiving chemotherapy. An independent drug safety monitoring board involved in the study recommended this course of action, which Roche’s drug safety committee endorsed, according to Roche.

	In this trial, enrolled patients were randomized  to receive CERA 6.3μg/kg, 9μg/kg, or 12μg/kg subcutaneously every 3 weeks, or darbepoetin alfa according to the approved local label (either 6.75 μg/kg subcutaneously every 3 weeks, or 2.25 μg/kg every week).

	Roche halted enrollment because of “a numerical imbalance in the number of deaths across the four arms of the study (three arms with CERA and one arm with darbepoetin alfa).” The investigators reported all deaths among study enrollees were unrelated to the study drugs.

	Roche representatives said in a written statement that there “appears to be no association of these events to excessive hemoglobin levels or the administered doses based on the current review of the data.” They said they have not observed similar types of imbalance in previously completed studies with CERA in cancer patients receiving chemotherapy.

	A review of patient data showed that there were imbalances in baseline disease characteristics—including extent of metastatic spread, presence of liver metastases, and incidence of chronic obstructive pulmonary disease&mdash;among enrollees in the different arms of the trial.

	To date, 153 patients have been enrolled and randomized. Patients who are already enrolled will continue with the study as planned. The safety data from the patients continuing in the study will be closely monitored by Roche working with the Drug Safety Monitoring Board. Roche is further investigating the potential causes for the imbalances in the study arms.

	The temporary suspension of recruitment and the decision to allow currently enrolled patients to complete the 12-week study period will permit an in-depth analysis of the data to determine potential confounding factors and potentially allow recruitment to be restarted.

	Roche has informed all investigators involved in the study of its decision and is working closely with them. The company has also informed health authorities in the countries where the study is taking place.

                                                                                                                                                                                              — John D. Zoidis, MD

Companies in the news:  1) AVAX and CTCA Collaborating for Cancer Therapies  2) Full Speed Ahead for GPC Biotech's Satraplatin 3) Bristol-Myers Squibb Company / Adnexus Therapeutics:     Collaboration  for New Oncology Compounds, and more

The Industry Insider: April 2007

 Largest Cancer Genome Study Implicates More Mutations than Previously Thought

he broadest survey yet of cancer genomes suggests that the number of mutated genes that drive development of the disease is greater than previously thought. Along with the driver mutations, each cell type carries many more passenger mutations that have no consequence on cancer formation. The study thus implies that the challenge lies in the ability to siftthrough mutations and decipher the drivers from the passengers.

	“The human genome is a vast place and this, our first deep systematic exploration in cancer, has thrown up many surprises,” noted Mike Stratton, co-leader of the Cancer Genome Project at the Sanger Institute.

 that they sequenced more than 250 million letters of DNA code, covering more than 500 genes and 200 cancers. The team identified possible driver mutations in 120 genes, most of which had not been seen before.

	“It turns out that most mutations in cancers are passengers,” explained Dr. Andy Futreal, also co-leader of the Cancer Genome Project. “However, buried amongst them are much larger numbers of driver mutations than was previously anticipated. This suggests that many more genes contribute to cancer development than was thought.”

	To distinguishing between the driver and passenger mutations, scientists will have to analyze much larger numbers of each cancer type. Faster DNA sequencing technologies will be important to achieve the scale of study needed.

	The genes surveyed were of the kinase type, and Dr. Futreal said that one finding was that a group of kinases involved in the Fibroblast Growth Factor Receptor signaling pathway was hit much more than expected, particularly in colorectal cancers.

	“This is a beautiful study,” commented Victor Velculescu, director of Cancer Genetics, from the Ludwig Center for Cancer Genetics and Therapeutics and Johns Hopkins University Kimmel Cancer Center. “It nicely shows the power of unbiased large-scale mutational analyses in human cancer and points to a large number of unappreciated protein kinases that appear to be important in tumorigenesis.”

	The team also found that the mutations carry coded messages within them. The type of mutation varies between individual cancers, reflecting the processes that generated the mutations, some of which were active decades before the cancer showed itself. Although some patterns are understood, such as the signatures of damage from UV radiation or cancer-causing chemicals in tobacco, others still require decoding.

	“The time is right to apply the powerful tools of genomics to obtain a comprehensive view of what goes wrong at the DNA level in cancer,” remarked Francis S. Collins, MD, PhD, director of the National Human Genome Research Institute at the NIH.

                                                                                                                                                                                                 — Querida Anderson

%u25BA Memorial Sloan-Kettering Cancer Center

 Death Rates for Smokers Are Not Improved Although CT Screening Increases Early Diagnosis

lthough CT screening found nearly three times as many lung cancers as predicted, researchers found no corresponding decrease in specifically detecting advanced lung cancers or in deaths from the disease.

	The multicenter study was led by researchers at 

, who published their findings in the March 7 issue of the 

Journal of  the American Medical Association

	“Ours is the first study to ask whether detecting very small growths in the lung by CT is the same as intercepting cancers before they spread and become incurable,” explained Peter B. Bach, MD, MAPP, a lung physician and epidemiologist at Memorial Sloan-Kettering and the study’s first author. “We found an answer and it was no.”

	The study enrolled 3,246 asymptomatic men and women with a median age of 60 who had smoked or still smoked for an average of 39 years. Starting in 1998, the patients had an initial CT scan and then at least three subsequent annual exams at either the Mayo Clinic in Minnesota, the H. Lee Moffitt Cancer Center & Research Institute in Florida or the Instituto Tumori in

	The researchers followed the volunteers to see how many had cancers detected by screening and how many had surgery to remove them. To ascertain rate of death from lung cancer, they used government records to follow the study participants for five years.

	The team analyzed the effect of CT screening on the frequency of lung cancer cases, lung cancer resection, advanced lung cancer cases, and deaths from the disease. They compared their findings with what would have occurred in the absence of screening, according to a set of prediction models. Dr. Bach and Colin B. Begg, PhD, chair of the department of epidemiology and biostatistics at Memorial Sloan-Kettering, developed the statistical method for the study. The models were designed to apply to high-risk individuals, whose risk factor values fall within the following ranges: age 50 to 80 years, smoked for between 25 and 60 years, averaged between 10 and 60 cigarettes per day and if quit, had quit within the past 20 years.

	The comparison found that CT screening increased detection three-fold and surgery 10-fold. The researchers diagnosed 144 cases of lung cancer, whereas 44.5 cases were expected. A total of 109 lung cancer surgeries were performed compared with the model prediction of 10.9. Overall, 96 of the cases detected were either stage I or stage II and 42 were advanced lung cancer. The model predicted 33.4 incidences of such later-stage disease. Hence, people with stage III or IV lung cancer were not much more likely to have their disease detected through the CT scanning format of this study than without  screening altogether.

	Similarly, while overall 38 deaths occurred due to lung cancer after the first year of screening, the model predicted a close 38.8 deaths. For the 67% of participants detected with early-stage lung cancer, only 12 died from non—small cell lung cancer during the study. Instead, the majority of individuals who died from the disease did not have their cancer detected when it was in an early stage and likely to be curable: 13 (34%) of those who died from lung cancer were initially diagnosed with stage III or stage IV non–small cell lung cancer, 7 (18%) were diagnosed with small cell lung cancer and 6 (16%) had no documented diagnosis of lung cancer prior to their death from lung cancer.

	“With lung cancer the number one cause of cancer deaths in the United States, the medical profession continues to seek an effective and safeapproach to prevent deaths from this disease. According to our study, CT screening may not be it,” stated Dr. Bach.

                                                                                                                                                                                                — Querida Anderson

 Rice Bran Reduces Intestinal Adenomas in Mice

esearchers in the United Kingdom have found that a suitable daily dose of stabilized rice bran reduces precancerous adenomas in the stomach and large intestine of mice. The results, published online on January 9 in the 

, confirm the dietary benefits of rice bran, which has been thought to have long-term health benefits and the potential to prevent diseases.

	The study was led by Andreas Gescher, a professor in the department of cancer studies and molecular medicine at the 

 in the UK. The stabilized rice bran used in the study was produced by El Dorado, CA-based NutraCea.

	Gescher and his colleagues tested the effects of a diet containing 30% stabilized rice bran on mice with breast, prostate and intestinal cancer—a comparable diet in humans would contain about 200 grams of rice bran per day. They found that mice on the diet that included rice bran had an average reduction of 51% in the number of intestinal adenomas compared to mice on a control diet. Rice bran also decreased intestinal hemorrhage in the mice. In addition, the researchers found that when rice bran in the mice diet was reduced from 30% to 10%, the number of adenomas did not decrease significantly. Gescher said that the reduction of intestinal adenomas was dependent on the fiber content of the bran. Rice bran did not have any effect on the development of prostate or breast cancer.

	According to NutraCea, the fiber content of their stabilized rice bran product is approximately 29%. Since the effects of the rice bran against adenomas depends on the fiber content, the company believes that their product Fiber Complex, which is the insoluble fraction of the rice bran and contains 43% fiber, would lead to even more significant effects.

                                                                                                                                                                                              — Prachi Patel-Predd

 Holographic Images Show Tumor Response to Drugs

physicists presented the first 3-D images showing the response of tumors to anticancer drugs at the American Physical Society meeting on March 6. The researchers have developed a new digital holographic imaging system to peek inside tumor cells.

	The holographic imaging system comprises of a laser and a charged couple device chip—a microchip that captures images in digital cameras. Holography works by bouncing a light beam offan object and onto a recording medium such as a CCD chip and another light beam directly on the recording medium. This creates a pattern of bright and dark spots that change at the slightest movement of the object.

	The Purdue researchers use the same principle, reflecting light offorganelles inside cancer cells that they grew in a laboratory. Organelles are specialized structures that play a key role in uncontrolled cell division and are a common target of anticancer drugs. Because organelles are typically in constant motion, they caused the bright and dark pattern to shimmer. But when the researchers added the anticancer drug colchicine to the cells, the drug limits the movement of organelles. “As the anticancer drug works, there is less motion inside the cell and the shimmer effect is reduced,” said David Nolte, a professor of physics at Purdue who led the research. “This can be seen right on the screen.”

	The imaging system could have advantages in biological applications. It is sensitive to movements as small as half a micrometer. Besides, it can be used to visualize a large range of object sizes, from the sub-micrometer motion inside cells to larger, tens of micrometers sections of tumors.

	“Biologists currently have to look at things on the cellular level through microscopes,” Nolte said. “With this technology, we now can detect things on the cellular level and the tissue scale at the same time.”

                                                                                                                                                                                             — Prachi Patel-Predd

%u25BA St. Jude Children's Research Hospital

 New Insight on Mutations Could Lead to Pediatric Leukemia Treatment

reviously unsuspected genetic mutations that contribute to pediatric acute lymphoblastic leukemia (ALL) tumors could lead to novel methods for treating ALL, according to researchers at 

in Memphis, TN. Acute lymphoblastic leukemia is the most common cancer in children, in which immature white blood cells rapidly multiply and become cancerous instead of developing into lymphocytes.

	The research team used DNA microarray chips to investigate more than 350,000 single nucleotide polymorphisms—variations in a single nucleotide between two DNA sequences&mdash;in tumor samples from 242 pediatric patients with ALL. They found that 40% of patients had mutations in one of three genes that govern the normal differentiation and development of immature white blood cells into lymphocytes. In a paper published online in 

 on March 7, the researchers show that the PAX5 gene was most frequently mutated—it had variations in almost a third of the patients. Other genes, including EBF1 and Ikaros, which play important roles in the formation of lymphocytes, also had mutations.

	The actual extent of mutations could be much higher, the researchers said.

	“Although the identification of such a high frequency of mutations in this pathway was surprising, it is important to note that the approach used provides a lower limit of the true frequency of these mutations, since not every gene in this pathway could be accurately analyzed using this methodology,” said James Downing, scientific director and chair of the Pathology Department at St. Jude who led the work.

	Understanding why progenitor white blood cells get stuck in their immature cancerous stage could lead to new therapies that eliminate the cells.

	“If we could design a drug that bypasses the roadblock to differentiation, we could push these cells to become fully mature B lymphocytes,” Downing said. “And then the body would recognize them as defective B lymphocytes and destroy them.”

%u25BA MESA   Institute for Nanotechnology, University of Twente

MESA  Institute for Nanotechnology of the University of Twente

, Enschede, The Netherlands, have developed a new “caged” DNA system that combines DNA macromolecules with polymers containing iron, which represents a novel drug delivery system for gene therapy.

	The walls of the cages are built step by step. DNA has a negative electrical charge, while the iron-containing polymer is  positively charged. In addition, DNA is much more rigid than the polymer. When bound together by electrostatic forces, the polymer wraps around the DNA and forms a very stable couple with it.

The Academy delivers the latest news on biotechnology and oncology research, providing a link between the clinical world of cancer care and the university researchers who are pushing farther into knowledge and discovery.

The Academy: April 2007

	Bill To Solve Reimbursement Problems Introduced to House of Representatives

ew legislation that addresses solutions to problems with Medicare reimbursement for cancer care has been introduced in the House of Representatives. The legislation—known as the Community Cancer Care Preservation Act of 2007 (HR 1190)&mdash;is

	being cosponsored by Representatives Artur Davis (D-AL) and Jim Ramstad (R-MN).

	Representatives Davis and Ramstad, who both sit on the House Ways and Means Committee, have heard first-hand from practices about the problems with Medicare reimbursement for community cancer care. These members have visited community cancer clinics in their districts, have met with the leadership of the Community Oncology Alliance (COA), and have been very involved in understanding the issues. Mr. Ramstad sponsored legislation addressing this issue in the prior session of Congress.

	HR 1190 seeks to address the key problems with drug and services reimbursement, including:

	• Elimination of “prompt payment” discounts

	  sales price (ASP) so that ASP is not artifcially

	• Removal of the 6-month lag in ASP so

	  unfairly subsidizing the Medicare system

	  There were more than 100 price increases

	• Creation of payment codes for essential

	  components of quality cancer care that

	  Medicare does not currently reimburse;

	• Restoration of appropriate payment for

	  the first hour and subsequent hours of

	The use of ASP to determine reimbursement is not without controversy, however. According to the National Association of Chain Drug Stores, using ASP to determine pharmaceutical reimbursement under Medicare Part B, rather than Average Wholesale

	Price (AWP), will have a significant negative impact on pharmacies. This negative result will be further magnified and  multiplied if other public and private prescription drug programs such as a Medicare outpatient drug benefit, Medicaid, private pharmacy benefit managers (PBMs), insurance companies, the Department of Defense’s Tricare program, and the Federal Employees Health Benefit Program (FEHBP), use ASP rather than their current reimbursement system.

	The COA has worked with Representatives Davis and Ramstad and has expressed appreciation for their support for community

	cancer care. More details on the bill are expected in the near future.

                                                                                                                                                                                             — John D. Zoidis, MD

NCI Budget Cuts Affecting Cancer Research

he recent congressional decision on the 2007 budget for the National Cancer Institute (NCI) keeps the budget essentially the same as last year, which means a flat funding for more than two years in a row that is leading to cuts in key cancer research across the country.

	In February, Congress approved a continuing resolution that finalized the NCI’s budget at $4.79 billion. This is an increase of $46 million over the 2006 budget, which members of the cancer research community say is an insignificant increase. This is “essentially a cut because in a situation where you have a flat fund over a period of two to three years, inflation begins to take over and so effectively your spending power is less,” Deborah Kamin, senior director for cancer policy and clinical affairs at the American Society of Clinical Oncology (ASCO) told 

. “What the cancer research community has done in response is begin to pull back and tighten their belts to live within the budget constraint.”

	The effective budget cut is adversely impacting research at Cancer Cooperative Groups, a network of institutions and practices across the country that conduct cancer clinical trials funded by the NCI. According to ASCO, 95 new trials, comprising 60% of all new trials that were planned for this year, will not be started or will face significant cutbacks. In addition, Kamin said that the cancer cooperative groups have also been told to reduce patient accrual to their existing trials.

	Needless to say, the cancer research community is expressing concern, and ASCO is calling for at least a 7% increase in the NIH budget to keep pace with inflation. The society is also taking a lead in speaking with the cancer community and making legislators aware of the full impact of the NCI budget cuts on cancer research, Kamin said. “[We are] finding out which trials are not going to happen, how many, what’s the real impact, and share that information with congress so they understand the full impact of even flat lining the budget.”

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Senate Panel Weights Pros and Cons of Generic Biologics for Cancer

n mid-March, the US Senate weighed arguments concerning the pros and cons of generic biologic drugs for cancer and other diseases. Legislation that would give the FDA legal authority to approve alternative versions of biologic drugs after patents expire is being considered by the Senate Health, Education, Labor and Pensions Committee. The core issue is the cost savings with generics versus the documented safety of brand biologics. Also at issue is whether generic versions of biologics can undergo an abbreviated approval process without first conducting clinical trials.

	More than 20 years ago, congress gave the FDA power to clear generic versions of conventional drugs, but did not address  costly medicines derived from living cells, such as Amgen’s Epogen®/Aranesp® and Johnson & Johnson’s Procrit®—all proprietary formulations of epoetin alfa.

	According to Jay Siegel, head of research for Johnson & Johnson’s biotechnology business, “You just can’t take a molecule that you don’t know what it is and market it to the people. It’s too risky.” Senators Hillary Clinton (D-NY) and Charles Schumer (D-NY)—sponsors of the bill&mdash;said their plan allows the FDA to decide how much testing is needed on a case-by-case basis. A similar measure has been introduced in the US House of Representatives by California Democrat Henry Waxman.

	Employers and insurers consider clearing a path for generic biologics as a means of reducing escalating health care costs. According to Sid Banwart, vice president for human services at Caterpillar, Inc., “This is our single the trend is simply not sustainable.”

	Supporters believe Congress should act soon on this issue. “This is an area that if we don’t address, everything else we do in healthcare is not going to be sufficient because we can’t keep up,” remarked Clinton.

	Republicans advocate a more cautions approach. “Any time we start legislating on complex scientific issues and don’t know all the facts, we risk endangering lives,” explained Senator Mike Enzi (R-WY), the committee’s ranking member.

                                                                                                                                                                                               — John D. Zoidis, MD

n February, two new bills were introduced in Congress with the goal of protecting quality cancer care. On February 15, Reps. Lois Capps (D-CA) and Tom Davis (R-VA) reintroduced the Comprehensive Cancer Care Improvement Act of 2007. The legislation aims to give physicians the resources they need to provide patients with quality cancer care. The bill would establish a new Medicare service for cancer planning from diagnosis through treatment to survivorship. It also includes provisions for the improvement of symptom management and palliative care. The proposed legislation is supported by the National Coalition for Cancer Survivorship, members of the patient advocacy community, and the American Society of Clinical Oncology.

	Reps. Carolyn McCarthy (D-NY), Gene Green (D-TX) and Joseph Pitts (R-PA) introduced another cancer care-related bill on February 28. The Access to Medicare Imaging Act of 2007 would delay additional cuts for Medicare imaging over the next two years. It would require the Centers for Medicare and Medicaid Services to stop additional cuts that went into effect at the start of 2007. Moreover, the proposed legislation calls for the Government Accountability Office to evaluate the impact of the cuts on patient access to care and quality services. The bill has 38 co-sponsors in the House and is expected to be introduced in the Senate soon.

CDC Panel Chair Says No to HPV Vaccine Mandate

on Abramson, the chair of the Centers for Disease Control and Prevention’s (CDC) advisory committee on immunization practices, said in late February that lawmakers should not make the human papillomavirus (HPV) vaccine mandatory. The CDC advisory committee had recommended that girls ages 11 and 12 receive the vaccine soon after the US Food and Drug Administration (FDA) approved Merck’s HPV vaccine Gardasil® for sale and marketing in July 2006.

	Merck’s Gardasil and GlaxoSmithKline’s Cervarix™ were shown in clinical trials to be effective against two strains of the sexually transmitted HPV that together lead to about 70% of cervical cancer cases. More than 20 states and Washington, DC are considering making the vaccine a requirement for girls and women. The issue has raised protests from many opposing fronts: parents who say the vaccine requirement would interfere with control over their children, groups that oppose legislative  vaccination requirements, and conservative religious groups that say it would encourage premarital sex. The cost of the vaccine—taken in a series of shots at $120 each&mdash;has also sparked criticism, although about 45% of children would be eligible for free vaccines under the federal Vaccinations for Children program, and a few states are considering offering the vaccine at no

	Abramson said that he opposes requiring the vaccine because HPV is not a contagious disease and he is not sure that states can afford to inoculate all students. He also said that he and other panel members told Merck not to lobby lawmakers to require the vaccine for school attendance. “The vaccines out there now are for very communicable diseases,” Abramson said. “A child in school is not at an increased risk for HPV like he is measles.”

	Merck, who had begun to lobby state legislatures last year, suspended its lobbying efforts early in February under pressure from parents, public health officials and patient advocacy groups.

This month's Fed Focus highlights such topics as Medicare reimbursement for cancer care and NCI budget cuts that affect cancer research.

Politics & Policy: April 2007

Avalon Could Earn More Than $200M in Deal with Merck & Co.

valon Pharmaceuticals, Inc. and Merck & Co., Inc. will together identify and develop inhibitors for a validated cancer target that has been tough to test outside the cellular context, according to Kenneth C. Carter, PhD, president and CEO of Avalon.

	Investors reacted favorably to the news. On the day of the announcement, Avalon (AVRX) shares jumped 94 cents, or 20.6%, to $5.51 in morning trading on the Nasdaq Stock Market. Merck (MRK) added 47 cents, at $44.78, on the New York Stock Exchange.

	The pharmaceutical industry has been focused on a drug discovery paradigm that starts with identifying a specific validated molecular target and testing them to identify candidates that can be used for therapeutic intervention, notes Dr. Carter. “Many of these targets are enzymes which facilitate biochemical reactions within cells that can be removed from their cellular context and tested in a high-throughput screening,” he said. “However, the majority of validated targets are not amenable to functional

	testing outside the cellular context. These ‘intractable targets’ have frustrated drug developers for decades.”

	Dr. Carter also noted that, “The combination of Merck’s considerable drug discovery and development capabilities and Avalon’s unique approach for targeting otherwise intractable cancer pathways should result in the identification of first-in-class drug candidates.”

	The AvalonRx® will be used to screen a select set of compounds from Merck’s compound library and identify hits against this target. Avalon will optimize compounds to a preclinical candidate-selection stage. Merck will be responsible for the clinical development, regulatory approval and commercialization of product candidates.

	According to the drug discovery, development and commercialization, Avalon may receive milestones exceeding $200 million and royalties on marketed products. The timeline for discovery and preclinical portions of the collaboration is expected to be three years, according to Dr. Carter.

	Added Lex Van der Ploeg, PhD, vice president, Merck Research Laboratories and site head, Merck Boston, “We are very pleased with this agreement, and believe this collaboration has potential to provide significant synergy in drug discovery.”

                                                                                                                                                                                          — Querida Anderson

XiGENE, Inc. (OXGN) is a clinical-stage biotechnology company that develops novel therapeutics for the treatment of cancer and eye disease. OXiGENE recently reported operational and financial results for its fourth quarter and fiscal year 2006.

	For the fourth quarter of 2006, OXiGENE reported a net loss of approximately $3.4 million, or $0.12 per share, compared to a net loss of approximately $3.4 million, or $0.16 per share, in the fourth quarter of 2005. For the 12-month period ending December 31, 2006, OXiGENE reported a net loss of approximately $15.5 million, or $0.56 per share compared to a net loss of approximately $11.9 million, or $0.61 per share in 2005.

	As of December 31, 2006, OXiGENE reported cash, cash equivalents, and marketable securities of approximately $45.8 million, compared with approximately $58.9 million at the end of December, 2005. Cash utilization for 2007 is anticipated to be between approximately $16 and $22 million in support of the OXiGENE’s ongoing research and development efforts.

	According to Dr. Richard Chin, president and chief executive officer of the company, “OXiGENE has developed a clear and focused strategy, demonstrated sound execution on key scientific and development projects and committed to establishing strong partnerships with the addition of a chief business officer. We are pursuing anaplastic thyroid cancer as our lead targeted indication, and we believe we have a development strategy that will make CA4P the first vascular disrupting agent on the  market.”

	CA4P (combretastatin A4 phosphate) is a vascular targeting agent that exerts its anti-angiogenic effect by targeting unstable budding neovessels in tumors. CA4P selectively targets endothelial cells, but does not target smooth muscle cells. It also induces regression of unstable, newly formed vessels by disruption of vascular endothelial-cadherin (VE-cadherin) signaling. VE-cadherin is a protein found at the junctions of overlapping regions of endothelial cells, and plays a key role in many aspects of vascular function, including endothelial cell survival, cell migration, cell proliferation, and assembly into vessel-like structures. Mechanistic studies have demonstrated that CA4P has anti-tumor and antiangiogenic activity in a variety of tumor types.

	Commenting on the year ahead, Dr. Peter Harris, chief medical officer of OXiGENE stated, “For our oncology program, our focus will be to enroll our first patient in the advanced thyroid cancer phase III trial by the end of the first half of 2007.”

	Future research may further elucidate the mechanisms whereby CA4P exerts its anti-tumor effect, potentially opening up new avenues of research to selectively target tumor neo-vessels and increase the therapeutic window of anti-angiogenic agents.

Physicians' Financial News focuses on news-making and/or notable companies in the oncology/biotechnology sector. In this issue:  1) Avalon Could Earn More Than $200M in Deal with Merck & Co. 2) OXiGENE Sets Fiscal 2007 Priorities 3) Genentech Shares Fall Nearly 3% on Avastin Study, and more

John D. Zoidis, MD

Articles

News Reports; March 2007

The Industry Insider: April 2007

The Academy: April 2007

Politics & Policy: April 2007

Physicians' Financial News for April 2007

The Virtual Window: Clinical Trial Reports--April 2007

News Reports: May 2007