Nanotech imaging, molecular fingerprints and signatures hold promise for cancer

03/26/04

Genomics, proteomics, and nanotech biomedical engineering lead to precise early detection in prostate and ovarian cancer, and metastasis of breast cancer

ORLANDO -- Scientists described three novel advances aimed at early detection of cancer--a critical key to controlling or curing the disease. Through analysis of molecular fingerprints or genetic signatures, scientists have devised technology to identify ovarian or prostate cancer. A third technology produces magnetic resonance portraits that define the extent of early metastasis in breast cancer. Researchers described advances in imaging technology, proteomic and metabolomic analysis that may lead to improved quality of life for patients with breast, ovarian or prostate cancer.

The new technologies were presented at the today 95th Annual Meeting of the American Association for Cancer Research here today.

Lymphatic drainage imaging of the breast cancer in mice using the micro-magnetic resonance mammo-lymphangiography using a nano-size contrast agent: Abstract No. BA-4

A new advance in nanotechnology will allowphysicians to precisely track the early spread of breast cancer cells to surrounding lymph ducts and nodes, helping to better define or even eliminate surgery.

The development is based on nanotech engineering of G6, a contrast agent used in magnetic resonance imaging (MRI), said Hisataka Kobayashi, M.D., Ph.D., staff scientist in the Molecular Imaging Program at the National Cancer Institute of the NIH.

Using G6 as a contrast agent, MRI technology visualizes metastases that have spread to the first and subsequent lymph ducts and nodes, thus defining the extent of surgery needed for the patient.

"In breast cancer patients, the presence of lymph node metastases greatly affects the prognosis, and the degree of surgical intervention needed," said Kobayashi. "If metastases have not advanced beyond the sentinel node, however, there is arguably no need to surgically remove extensive amounts of lymph nodes.

"With the knowledge of the exact location and extent of tumor infiltration in to the lymphatic system, the surgeon can minimize the incision," Kobayashi said. "This method offers hope of improving the quality of life after surgery by limiting the surgery and perhaps negating the need for further painful chemotherapy when metastasis is evident to be contained within the sentinel node and not in downstream lymphatic structures."

The key to maximizing performance of G6 as a contrast reagent resids in the structure of the lymphatic vessels and nodes, Kobayashi said. The molecule needs to be small enough to rapidly enter the lymph ducts in the lymph fluids, yet large enough to remain within the lymphatics and not leech out into capillary vessels. The Johns Hopkins and NCI team tested G6, a dense (240 kDa) molecule with a span of 9 nanometers. The agent was tested using clinically dedicated MRI instrumentation to evaluate clinical setting performance. The performance of G6 was observed in mouse models for breast cancer.

The researchers looked at the rate of flow of G6 through the lymphatics system from the tumor site to determine "ultimate" sentinel nodes and confirmed that those lymph nodes are at greatest risk for initial spread of metastasis of breast cancer cells. Their technology detected 1 millimeter tumors in 3 millimeter lymph nodes, a 100-fold increase in the precision of detecting tumors than possible with existing conventional lymph node imaging technology. The resolution of this imaging technology distinguished both lymph nodes and ducts, which no other currently used method can discern. Furthermore, the technology visualized lymph nodes that had been totally displaced with cancer cells. Previously existing technology is unable to detect nodes fully occupied with cancer cells.

"This method can tell both the location of true sentinel lymph nodes and the presence or absence of metastatic cancer in those nodes within an hour by a single MRI study," Kobayashi said. "We validated the performance of this agent on the clinical machinery in the mouse model, and we expect the drug to perform as well in the human.

"If the drug is approved for human use, we can start clinical trials as soon as the go-ahead is given," Kobayashi said.

Diagnosis of prostate cancer with intact tissue magnetic resonance spectroscopy: Abstract No. 1069

Distinct molecular 'fingerprints' uniquely produced by cancerous prostate cells indicate how aggressive the disease is in individual patients, a team of Harvard University scientists revealed today.

"Cancerous prostate cells produce molecular metabolic 'fingerprints' that differ from the metabolic 'fingerprints' of healthy prostate cells," said Leo L. Cheng, Ph.D., Massachusetts General Hospital, Harvard Medical School.

"Through the use of proton magnetic resonance spectroscopy technology with high resolution magic angle spinning, we were able to distinguish between healthy and cancerous tissues according to their metabolic changes," he added. The technology is more powerful and precise than conventional histological measures.

By reading the metabolic portrait from prostate samples, the Harvard/MGH research team was able to determine the tumor aggressiveness. Magnetic resonance spectroscopy analysis of the tissue metabolic fingerprint correlated with the patient clinical status, such as the overall pathological features and stages.

This advance in technology can provide valuable information to patients and their clinicians before making treatment decisions regarding choices among surgery, chemotherapy, and radiation for prostate cancer.

Carrier albumin's binders in serum (CAB's): Detecting ovarian cancer: Abstract No. 4774

A unique set of proteins produced by ovarian cancer cells serves as a signature for malignancy and may translate to powerful early detection diagnostic assays, a NCI-FDA Clinical Proteomics Program researcher said.

Arpita I. Mehta, M.S., Howard Hughes Medical Institute Research Fellow and Tufts University Medical Student, identified a subset of proteins produced by ovarian cancer cells that differ in quantity and/or identity from the proteins found in normal healthy ovarian cells. Those proteins mark the presence of ovarian cancer and advance the quest to provide a means to differentiate between early and late stage ovarian cancer in women.

Mehta and colleagues examined proteins and peptides that travel in the blood attached to albumin, a large 'sticky' serum protein that acts as a carrier of bioactive molecules. By comparing the albumin-binding protein profiles from 115 ovarian cancer patients with 127 healthy women, Mehta and colleagues discovered clusters of proteins from cancer patients that differed radically from the protein profile found in healthy women. The results were extremely sensitive and specific. Candidate ovarian cancer diagnostic biomarkers emerged from mass spectrometric analysis of the patients' blood samples, such as proteins characterized at peaks consistent to 3100 or 6900 megahertz.

"The albumin found in blood is a bountiful source of unexplored diagnostic information," Mehta said. "By examining the proteomic pattern of proteins that bind to albumin, we stand to advance our opportunities for precise diagnostics of early stage ovarian cancer in women at high risk and throughout the population in general."

Ovarian cancer is often referred to as a "silent killer" due to lack of symptoms prior to the cancer advancing to a later stage--often stage III. It is the most lethal of gynecological cancers. More than 25,000 women will be diagnosed with ovarian cancer in the United States during 2004, and half of those patients will die from the disease within five years. Five-year survival is dramatically increased among women who are diagnosed in earlier stages of the disease. However, fewer women are diagnosed before ovarian cancer has advanced beyond stage one because the disease remains without obvious symptoms until late stage. Simple, specific and sensitive biomarker diagnostic assays that develop from mass spectrometric analysis of blood-borne proteomic arrays will help diagnose early stage development of ovarian cancer, Mehta said.

The albumin-binding biomarkers indicative of ovarian cancer were discovered by researchers from the National Cancer Institute of the NIH, the Center for Biologics Evaluation and Research at the FDA, the Howard Hughes Medical Institute, the Tufts University School of Medicine.

Source: Eurekalert & others

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