 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.

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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

Cell Genesys and Medarex Remain Positive on Combination Immunotherapy Study

	Cell Genesys, Inc. and Medarex, Inc. said that follow-up data from the ongoing phase I trial of Cell Genesys’ GVAX  immunotherapy for prostate cancer, administered in combination with Medarex’ fully human anti-CTLA-4 antibody, ipilimumab (MDX-010) were positive.

	“We continue to be encouraged by the interim results of this trial, which now include evidence for the durability of the anti-tumor responses along with the frequency of such responses, observations which we believe have not been previously experienced for a combination of immunotherapies in advanced prostate cancer,” stated Rob Dow, MD, chief medical officer of Cell Genesys.

	“Moreover, we believe these findings provide further support for our ongoing phase III trials of GVAX immunotherapy for prostate cancer.”

	A maximum tolerated dose for the combination therapy has not yet been defined. Immunomonitoring studies showed that the combination therapy enhanced T-cell and dendritic cell activity, which was more pronounced at the higher dose levels.

	To date, 12 patients with advanced prostate cancer completed treatment. Of the six patients treated in the two highest dose groups, anti-tumor activity was observed in five. Prostate-specific antigen (PSA) declines of greater than 50% were maintained in four of these patients for at least six months. The longest response is reportedly ongoing at more than 12 months. Moreover, evidence of anti-tumor activity has been observed in three of the PSA responders, including improvement of multiple lesions on bone scan, resolution of abdominal lymph node disease by CT scan and improvement in pain due to bone metastases. Additionally, two patients have had stable disease on bone scan for at least three months.

	This dose-escalation combination trial is currently expected to enroll a total of approximately 25 to 30 patients with metastatic

                                                                                                                                                                                             —Querida Anderson

Active Biotech Achieves Success with TASQ for Prostate Cancer

	Active Biotech reported positive data from its phase Ib study of TASQ for the treatment of prostate cancer. By step-wise dose escalation, a safedose of 1 mg/day was achieved. This represents a doubling of the previously reported maximum tolerated dose level.

	“We now have a very complete data set that constitutes a solid base to move into phase II clinical trials,” stated Sven Andreasson, president and CEO.

	The ongoing 10-week study comprises patients with HRPC. All patients entering the study had rising serum levels of prostate-specific antigen (PSA). PSA measurements were recorded and PSA velocity (PSAV) was calculated after 28 days of treatment. Out of six patients, five had greater than 50% decrease in PSAV compared to prior treatment. Of them, three exhibited a decrease in absolute PSA levels.

	The study is being performed at the urological clinics at the University Hospitals in Lund, Malmoe and Uppsala, Sweden. Phase II studies are scheduled to start during 2007.

	The objective of the TASQ project is to develop a pharmaceutical product that can be administered orally for the long-term treatment of prostate cancer. The market for prostate cancer is estimated at more than $3 billion a year, according to the company.

                                                                                                                                                                                              —Querida Anderson

Sunesis Initiates Phase I Trial of Small-Molecule CDK Inhibitor SNS-032

	Sunesis Pharmaceuticals, Inc. reported on March 6 that the first patient in a phase I clinical trial of SNS-032 in advanced B-cell

	malignancies has been dosed. SNS-032 is a novel, selective, and potent small-molecule inhibitor of cyclin-dependent kinase (CDK) 2, CDK7 and CDK9, and has been shown in preclinical and clinical studies to deplete cells of myeloid cell leukemia sequence 1 (MCL-1), a protein associated with cell survival, particularly in lymphomas and other B-lymphoid malignancies.

	Daniel C. Adelman, MD, senior vice president of research and development at Sunesis elaborated: “Based on non-clinical and phase I pharmacodynamic data of SNS-032 from our ongoing trial in patients with advanced solid tumors, we are eager to learn more about this promising anticancer compound in patients with hematological cancers. We are enthusiastic about initiating clinical trials in B-cell malignancies as we have seen evidence that SNS-032’s mechanism of action may be particularly well-suited to indications including multiple myeloma, chronic lymphocytic leukemia, and mantle-cell lymphoma.”

	The phase I trial of SNS-032 is a dose-escalation study designed to evaluate the safety and tolerability, as well as the preliminary anti-tumor activity of the agent in patients with advanced B-cell malignancies. The trial will also be used to  determine the maximum tolerated does in this setting, and will enroll 30 to 40 patients at three centers in the US. Preliminary results are expected by the end of 2007.

	Sunesis has a solid pipeline of preclinical- and development-stage product candidates in oncology focused on novel pathways and targets, including inhibition of the cell-cycle and survival signaling. Sunesis is currently conducting phase I-II clinical trials in lung cancer, ovarian cancer, and acute myeloid leukemia for its lead compound, SNS-595.

                                                                                                                                                                                               —John D. Zoidis, MD

Myriad Initiates Evaluation of Brain Cancer Drug that Crosses the Blood-Brain Barrier

	Myriad Genetics, Inc. initiated the first phase II trial of Azixa™ in patients with brain cancer. The company expects to enlist the participation of approximately 50-70 centers in the US and Europe.

	“We are pleased to continue the clinical development of this exciting compound,” said Adrian Hobden, PhD, president of Myriad. “The ability of Azixa to cross the blood-brain barrier gives us hope that because it can reach the site of the disease, it could be a more effective therapeutic than anything available today.”

	The standard of care for patients with glioblastoma multiforme (GBM) is primarily surgery and whole brain radiation. The five-year survival rate of the disease has remained unchanged over the past 30 years and stands at less than 3%, according to Myriad.

	The study is designed to determine the safety profile of Azixa and the extent of its ability to improve the survival of patients with GBM, the most common form of primary brain cancer. The trial will compare the survival of patients treated with Azixa to those treated with oxaliplatin and those treated with Azixa plus oxaliplatin.

	The trial will be an adaptive, open-label, multiple-dose study in patients with recurring or relapsed GBM. The first stage of the trial is designed to determine the safety and the maximum tolerated dose of Azixa in combination with oxaliplatin in  approximately 16 patients. The maximum tolerated dose of Azixa alone was determined during the earlier phase I trials. The second stage of the trial will then assess the survival of patients treated with the Azixa/oxaliplatin combination therapy compared to Azixa alone or oxaliplatin alone.

Second Lung Cancer Trial Adds Data to Novel Therapy

	Antisoma said the second, confirmatory phase II trial of its non-small cell lung cancer drug candidate showed a 50% response rate. Addition of AS1404 to chemotherapy was also well-tolerated.

	“The high response rate and favorable tolerability profile in this study support earlier data suggesting that AS1404 has real potential as a novel therapy for lung cancer,” commented Dr. Mark McKeage of the University of Auckland, New Zealand, a key investigator in both AS1404 lung cancer studies.

	This 30-patient trial tested a 1,800-mg/m² dose of AS1404 in combination with carboplatin and paclitaxel chemotherapy. Besides the 50% response rate, a further 43% of patients showed disease stabilization, while only 7% had progressive  disease as their best response.

	An earlier randomized controlled phase II study in lung cancer showed a fivemonth increase in median survival when 1,200 mg/m² AS1404 was added to carboplatin and paclitaxel. Initial data from controlled phase II trials in ovarian and prostate cancers also showed increased response rates.

	“AS1404 now draws support from four phase II studies across three different cancers, an excellent position to be in as we prepare the drug for phase III trials,” pointed out Glyn Edwards, CEO.

Adherex’ European Study Enhances Anticancer Candidate

	Adherex Technologies’ phase Ib/II study of single-agent ADH-1 showed good results. ADH-1 targets N-cadherin, a protein present on certain tumor cells and established blood vessels that feed solid tumors.

	The data includes 30 patients who received an aggregate of more than 200 doses, or 68 cycles, of ADH-1 given on a weekly schedule. Doses range from 150 to 2,400 mg/m². ADH-1 was well tolerated at all doses tested for periods of up to eight months, displayed predictable pharmacokinetics, and demonstrated hints of antitumor activity in five patients with advanced, chemotherapy-resistant cancer. A maximum tolerated dose has not yet been defined.

	“This European data is consistent with our prior clinical experience, showing ADH-1 to be well tolerated over a broad dosage range with hints of anti-tumor activity in a variety of tumor types,” said William P. Peters, MD, PhD, chairman and CEO. “Given the unexpected level of synergy of ADH-1 in combination with chemotherapy that we have reported from our preclinical studies, the clinical development of this drug continues fully on track.”

	In the European phase Ib/II study, three of 19 patients (16%) with ovarian/gynecological tumors experienced evidence of anti-tumor activity, one with an unconfirmed partial response (previously reported) and two with prolonged stabilization of their disease, which were previously rapidly progressive (eight and six months, respectively). Two other patients experienced stabilization of their disease, one with colorectal cancer and one with non-small cell lung cancer, each lasting three months.

Nexavar Could Soon Add Primary Liver Cancer to its Label

	Bayer Pharmaceuticals Corporation and Onyx Pharmaceuticals, Inc., under the recommendation of an independent data monitoring committee (DMC), decided to stop a phase III trial of Nexavar® in primary liver cancer and provide the patients enrolled access to the drug. Given that there are limited approved systemic therapies for this disease, the companies say they will continue discussions with health authorities worldwide regarding the next steps in filing for approval for the treatment

	“The observed superiority in overall survival for Nexavar-treated patients over patients receiving placebo demonstrates the efficacy of Nexavar in advanced primary liver cancer,” said Dr. Jordi Bruix, co-principal investigator and head of the Barcelona Clinic Liver Cancer Group, Liver Unit, Hospital Clinic Barcelona, Spain. Onyx’ shares rose 80% to reach $24.15 the day after the results were reported.

	The DMC reviewed the safety and efficacy data from the companies’ pivotal phase III trial in patients with primary liver cancer. It concluded that the trial met its primary endpoint resulting in superior overall survival in those patients receiving Nexavar (sorafenib) tablets versus those receiving placebo. The DMC also noted that there was no demonstrated difference in serious adverse event rates between the two treatment arms.

	Hepatocellular carcinoma is the fifth most common cancer in the world and is responsible for about 90% of the primary malignant liver tumors in adults.

	Nexavar is an oral multi-kinase inhibitor that targets the tumor cell and tumor vasculature. It is currently approved in nearly 50 countries, including the US, for the treatment of advanced kidney cancer.

	Threshold Pharmaceutical Inc.’s glufosfamide, which had received orphan drug status from the FDA late last year, has not met its primary efficacy endpoint in a phase III clinical trial. The primary endpoint of the trial was the overall survival in metastatic pancreatic cancer patients, measured as time from randomization for the trial until death. The drug, which was being tested as a second-line treatment, did not show a statistically significant improvement of overall survival as compared to best supportive care (BSC). At present, there are no approved second-line treatments for advanced pancreatic cancer.

The Clinical Trials reported in this issue include:  PHASE I: 1) Cell Genesys and Medarex Remain Positive on Combination    Immunotherapy Study 2) Active Biotech Achieves Success with TASQ for Prostate Cancer  PHASE II: 1) Myriad Initiates Evaluation of Brain Cancer Drug that Crosses the    Blood-Brain Barrier 2) Second Lung Cancer Trial Adds Data to Novel Therapy, and more

By Querida Anderson, Prachi Patel-Predd

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The Academy: April 2007

The Virtual Window: Clinical Trial Reports--April 2007