HOUSTON, July 28 — The inability to detect small ovarian tumors emphasizes the need for cancer-specific biomarkers that can detect more tumors at a curable stage, researchers suggested after analyzing statistical models of cancer growth, progression, and detection.

To achieve even 50% sensitivity, a biomarker assay would have to detect serous tumors that are 1/200th as large as the clinically apparent tumors typically used to evaluate candidate biomarkers, investigators reported online in PLoS Medicine.

However, the study also showed that the window of opportunity for detecting curable, serous ovarian cancer is surprisingly long.

“These cancers spend on average more than four years as in situ, stage I, or stage II cancers, and approximately one year as stage III or IV cancers before they become clinically apparent,” said Patrick O. Brown, MD, PhD, of Stanford University, and Chana Palmer, PhD, of the Canary Foundation in San Jose, Calif.

• Explain to patients that early detection of ovarian cancer will require tests that can detect small tumors.
• The findings of this study are based on a review of literature and statistical modeling.

“For most of the occult period, serous cancers are less than one centimeter in diameter and not visible on gross examination of the ovaries and Fallopian tubes. The median diameter of a serous ovarian cancer when it progresses to an advanced stage . . . is about three centimeters.”

“It is likely that some combination of new biomarkers and new approaches will be needed to meet the challenge of early detection,” they added.

When detected early, ovarian cancer has a favorable outlook, including a five-year survival of 70% to 80%. However, most tumors are detected in advanced stages, when patients have become symptomatic. Five-year survival for stage IV ovarian cancer is 15% or less.

The challenge of early detection is further complicated by the fact that “we know surprisingly little about the target for early detection of serous ovarian cancer,” the authors said. “What do lethal serous ovarian cancers look like during the ‘window of opportunity’ . . .?”

“By defining the what, when, and where of preclinical ovarian cancer, we can begin to rationally design an effective early detection strategy,” they added.

Data from studies of prophylactic bilateral salpingo-oophorectomy have provided some insights into the early natural history of ovarian cancer. Using data from published reports of the prophylactic surgery, the authors developed a model for the preclinical natural history of ovarian cancer and then evaluated its implications for early detection.

The analysis was limited to women with BRCA1 mutations, which can increase the lifetime risk of ovarian cancer to 40% for some women.

The review and analysis yielded five principal insights regarding early ovarian cancer:

• The prolonged period that serous ovarian tumors spend in situ and early-stage disease
• The small size (<1 cm) of serous tumors during most of the early-stage period
• Stage III-IV ovarian cancers have a median diameter of about 3 cm
• To achieve 50% sensitivity for detecting tumors before stage III, an annual screen would have to detect tumors no larger than 1.3 cm in diameter; and no larger than 0.4 cm for 80% sensitivity
• To reduce serous ovarian cancer mortality by 50%, an annual screen would have to detect tumors no larger than 0.5 cm in diameter

Most candidate biomarkers are tested against larger, symptomatic, advanced-stage ovarian tumors, the authors noted.

The study was funded by the Canary Foundation and the Howard Hughes Medical Institute. The authors reported no disclosures.

Primary source: PLoS Medicine

Source reference:

2009; DOI: 10.1371/journal.pmed.1000114.

CyDex Pharmaceuticals, Inc. announced that the U.S. GlaxoSmithKline .

In December 2008, CyDex received orphan-drug designation from the FDA for melphalan “as a high-dose conditioning treatment prior to hematopoietic progenitor (stem) cell transplantation.” This designation provides an important economic incentive, granting CyDex seven years of exclusive marketing rights.

“IND acceptance for Captisol-enabled melphalan is an important milestone for CyDex as we work to develop a portfolio of new drugs for the hospital acute care market,” said Theron E. Odlaug, CyDex’s president and chief executive officer. “We look forward to establishing a relationship with a strategic out-licensing partner to advance CDX-353 into the clinic and, longer-term, develop and commercialize this promising oncology product.”

Upcoming clinical studies are expected to begin with a phase 2(a) trial that compares the pharmacokinetics of CyDex’s CDX-353: Propylene Glycol-Free Melphalan HCL with Alkeran, and evaluate safety parameters. Alkeran is packaged as two separate vials that must be combined prior to injection and, due to its limited stability, administered immediately thereafter. CyDex’s version of melphalan is enabled by Captisol®, the company’s proprietary and patented sulfobutylether ?-cyclodextrin. Captisol-Enabled® melphalan is a one-vial formulation that does not contain harsh co-solvents and remains stable at room temperature for an extended period of time.

“CDX-353 is a novel form of melphalan that is more stable and could potentially allow for longer administration durations and slower infusion rates compared to current pre-transplant treatments for multiple myeloma,” said Parameswaran Hari, M.D., Clinical Director of the Adult Bone Marrow Transplant Program and Associate Professor of Medicine at the Medical College of Wisconsin. “These advantages have the potential to enable doctors to safely achieve a higher dose intensity of pre-transplant chemotherapy, which could lead to better therapeutic outcomes.”

Source
CyDex Pharmaceuticals, Inc.

Distinctive patterns of genes turned off - or left on - in healthy versus cancerous cells could enable early screening for many common cancers and maybe help avoid them, Medical College of Georgia scientists say.

Researchers are comparing chemical alterations, called DNA methylation, in the body’s basic building block in healthy colon, breast, brain and lymphatic cells and their cancerous counterpart to find telltale patterns that could one day be detected in the blood, urine or feces.

The patterns could give patients a heads up that lifestyle changes, or more severe intervention, is in order, says Dr. Kapil Bhalla, director of the MCG Cancer Center, Cecil F. Whitaker Jr., M.D./Georgia Research Alliance Eminent Scholar in Cancer and Georgia Cancer Coalition Scholar.

DNA methylation is a piece of a relatively new research field called epigenetics that looks more globally at which genes are turned off and on with an eye on early identification of some of the aberrant adjustments that enable cancer cells to thrive. Epigenetic changes actually are more common than the genetic mutations long known to put people at risk for cancer and other diseases and they are probably inherited as well, Dr. Bhalla says.

The early and apparently significant role of epigenetics in cancer has made the field a focal point for centers such as the MCG Cancer Center, which recently recruited two new epigenetics researchers with the help of the Georgia Cancer Coalition. The second floor of the three-year-old Cancer Research Center building, which is being finished with the help of $3.5 million from the Georgia Research Alliance, will house the Georgia Genomics/Epigenomics Center. In early 2008, the National Institutes of Health established an epigenomics program to coordinate such efforts to better understand how this method of gene regulation fits into normal development, aging, learning and memory as well as its role in cancer, obesity, depression and other disease.

DNA methylation inhibitors already are under study at MCG and other centers for a variety of cancers and blood disorders. Because tumor cells that result from aberrant changes shed their DNA into bodily fluids, non-invasive screening for a wide range of cancers could result be another result of this initiative, Dr. Bhalla says.

“We know that long before anyone tells you that you have a tumor, methyl groups have been put where they should not be,” says Dr. Keith D. Robertson, cancer epigeneticist and Georgia Cancer Coalition Scholar. “Every single tumor that anybody has looked at has aberrant change in DNA methylation. It’s clearly not random.”

The environment, from chemicals leached from plastic or cigarettes, along with diet, sleep patterns even physical activity levels can result in these epigenetic changes that contribute to cancer and other diseases. “The natural aging process, environment, our lifestyle really changes our natural mechanisms,” says Dr. Huidong Shi, epigenetics researcher who joined the MCG faculty this year and was recently named a Georgia Cancer Coalition Scholar.

But why tumors have so many epigenetic changes compared to healthy tissue is one of many mysteries. Whether the changes cause or result from tumors is another. “A lot of methylated genes we found in cancer are not naturally expressed in normal cells. So there are a lot of things we don’t know,” Dr. Shi says.

“A tumor is not only gaining methylation in certain areas and turning this gene off, it’s losing methylation in normally methylated areas,” echoes Dr. Robertson.

Dr. Shi has found, for example, a single gene that is methylated in the majority of the broad group of cancers called non-Hodgkin’s lymphoma. This methylated DLC1 is detectable in the plasma samples of lymphoma patients, making it a good candidate for the screening, says Dr. Shi who also is looking for these types of biomarkers in breast cancer and the aggressive adult brain tumor glioblastoma.

Dr. Robertson, who also works in breast cancer and brain tumors as well as colon cancer, is finding patterns of genes that regulate healthy cell differentiation are shut off in cancers. “These are genes that may need to be active during a certain period of development but once you have committed to become a certain cell type, like a skin cell, you need to turn the gene off,” he says.

“A lot of people think of cancer cells turning genes on, like oncogenes, that allow them to grow faster, evade immune surveillance, that sort of thing,” Dr. Robertson says. “There are also many genes that they also want to turn off, like ones that tell a cell to differenitate. For a cell to become cancerous, those kinds of things have to happen. Cells that don’t divide are not going to become cancer. They have to slip by the normal surveillance to survive and grow.”

To find the differences, that means always looking at healthy tissue to identify the standard and how that happens. “We want to know how a normal cell knows where to put methylation,” Dr. Shi says. “We don’t understand that. If you look in the genome there are regions that are always methylated and regions that never are. How does a cell know that? To understand what happens when it doesn’t, we need to know how the normal process is regulated.”

To get a total picture, these researchers also are looking at how the enzymes that methylate DNA work and how modifications in histones, the proteins around which DNA is wrapped, can leave a gene susceptible to methylation.

Additionally, Dr. Shi, who as a postdoctoral fellow 10 years ago worked alongside Dr. Tim H.M. Huang at the University of Missouri in Columbia, Missouri, to develop some of the first technology to examine genome-scale DNA methylation, is working with an NIH initiative to refine the technology to support the genome-wide DNA methylation sequencing effort.

“The work of Drs. Robertson and Shi is eminently important for our understanding of cancer, easily translated to patients and central to the Cancer Center’s mission to reduce cancer morbidity and mortality,” Dr. Bhalla says.

Both researchers joined the MCG faculty this year. Dr. Robertson completed his Ph.D. at The Johns Hopkins University School of Medicine in Baltimore and fellowship training at the Norris Comprehensive Cancer Center at the University of Southern California, Los Angeles, as well as the NIH’s National Cancer Institute. He was a faculty member at the University of Florida College of Medicine’s Shands Cancer Center before joining the MCG faculty.

Dr. Shi completed his Ph.D. and postgraduate work at Kyushu Institute of Technology in Japan. He then completed postdoctoral fellowships in biological engineering and pathology and anatomical sciences at the University of Missouri before joining that university’s faculty.

Source:
Toni Baker

Medical College of Georgia