New pretargeted radioimmunotherapy for colorectal cancer

ScienceDaily (June 6, 2011) — Investigators at SNM's 58th Annual Meeting are presenting results from a phase 1 clinical trial for a cancer therapy that has the potential to kill colorectal tumors with less destruction of healthy tissue. Further research could lead to the use of this radioimmunotherapy to eliminate residual cancer after surgery or as a standard treatment to keep tumors from returning or spreading to other organs.

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"Compared to the conventional way of guiding radiation to tumors with radiolabeled antibody, pretargeted radioimmunotherapy offers an attractive potential alternative because the delivery of therapeutic isotope is rapid and is separated from the long antibody delivery process, thereby reducing the harmful effects of radiation to the body, especially the bone marrow," says Rafke Schoffelen, MD, scientist of the study at Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands. "This results in an optimal scheme with maximum therapeutic effect and minimal side effects."

According to the American Cancer Society it is estimated that more than 141,200 Americans in 2011 will be diagnosed with colorectal cancer, and 48,000 will die of the disease. Colorectal cancer is currently the third most commonly diagnosed cancer and the third leading cause of cancer death for both men and women across the country. This form of cancer develops in the colon and rectum, usually as a result of polyps, or abnormal growths, that extend from mucous membranes in the lower gastrointestinal tract. Once cancer is detected, the most common treatments are surgery and chemotherapy, but chemotherapy is associated with many side effects, some of them serious and lifelong. This pretargeted radioimmunotherapy is engineered to be an effective alternative with far fewer adverse effects.

In recent years the development of radioimmunotherapy has led to increasingly targeted cancer therapies that combine antibodies pinpointing specific physiological processes of the cancer and medical isotopes that deliver a dose of radiation to the cancer tissue. Pretargeted radioimmunotherapy takes this a step further by breaking the therapy into two phases. In the first phase, an antibody is infused that recognizes both an antigen from the tumor and the building blocks of proteins that serve as a vehicle for the radioisotope. When the antibody has cleared the rest of the patient's system, leaving only the tumor-bound antibody, a second phase is administered in the form of an injected small protein labeled with the medical isotope. The drug binds with the already tumor-bound antibody and delivers the radiation dose. The fraction of the drug that is not bound is quickly cleared from the rest of the body by the kidneys and out through the urine.

The objective of this study -- the first of its kind to treat patients with metastatic, or spreading, colorectal cancer with pretargeted radioimmunotherapy -- was to improve patients' prognosis without compromising their quality of life. It is conducted in collaboration with Garden State Cancer Center, Belleville, Immunomedics Inc. (NASDAQ: IMMU) and IBC Pharmaceuticals Inc. of Morris Plains, N.J., developers of the pretargeting mechanism and reagents.

First, patients were administered a test-cycle to map the path and predict the radiation dose of the subsequent therapy injection. The antibody, TF2, was infused followed by the small protein, IMP288, carrying a non-therapeutic isotope, 111In, which was measured by whole-body planar and single photon emission computed tomography imaging. Patients were then administered TF2 again, and the therapeutic isotope and agent 177Lu-IMP288. Research showed effective targeting of tumors and minimal healthy tissue damage, which could lead the way for further studies with higher or multiple dosing strategies and greater targeting of cancer tissue.

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The cellular root of colorectal cancers?

ScienceDaily (June 10, 2011) — Researchers at Children's Hospital Boston have found a marker called ABCB5 that both tags a small proportion of cells within colorectal cancers and fuels resistance in those cells to standard treatments. The results indicate that eliminating ABCB5-expressing cells is crucial for successful colorectal cancer treatment, while adding to the growing body of evidence for a theory of cancer growth called the cancer stem cell hypothesis.

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An international team led by Brian J. Wilson, PhD, Tobias Schatton, PhD, and Markus Frank, MD, of the Transplantation Research Center at Children's Hospital Boston, and Natasha Frank, MD, of the VA Boston Healthcare System and Brigham and Women's Hospital, and colleagues at the University of Wurzburg in Germany reported the findings online in the journal Cancer Research on June 7, 2011.

An estimated 141,000 Americans will be diagnosed with colorectal cancer this year. While its mortality has been dropping over the last two decades thanks to screening and improved treatment options, colorectal cancer is still the second leading cause of cancer-related death in the United States.

Recognizing ABCB5's role as a marker of tumor recurrence in melanoma and liver cancer, and knowing from previous studies that the gene for ABCB5 is also active in colorectal cancer, the Franks' team studied the protein's expression in both normal and cancerous colorectal tissue specimens. They found that ABCB5 is found only rarely in healthy colorectal tissue, but is present at levels 23 times greater in cancerous tissue.

Underscoring its preferential expression on stem cells, ABCB5 was frequently accompanied on both healthy and cancerous cells by a second protein, CD133, which is thought to be a marker of both healthy intestinal stem cells and colorectal cancer stem cells. CD133 is also associated with aggressiveness in colorectal cancer.

To understand ABCB5's role in treatment resistance, the team examined biopsies gathered from colorectal cancer patients both before and after treatment with 5-fluorouracil (5-FU), a standard chemotherapeutic for this tumor. They found that the percentage of cells expressing ABCB5 increased more than five fold after treatment.

Using a mouse model of colorectal cancer, the researchers also found that cells expressing ABCB5 were markedly resistant to 5-FU. Knocking down ABCB5 expression both blocked the growth of these cells and restored their sensitivity to the drug, showing that ABCB5 is not only a marker of treatment resistance but actually drives it.

"With ABCB5, we have a molecule that is present at higher levels in colorectal cancers than in healthy cells, that marks the subset of cancer stem cells in human patients that will resist therapy, and that mediates that resistance at a functional level," said Markus Frank, a staff scientist Children's Department of Medicine and an assistant professor of pediatrics at Harvard Medical School. "It's a new mechanism of 5-FU resistance with very significant translational and therapeutic relevance," added Natasha Frank, a research associate at Children's Hospital Boston, an associate physician in the Division of Genetics at Brigham and Women's Hospital, and director of the Genetics Clinic at the VA Boston Healthcare System. "We think that these are the cells that need to be eliminated for successful treatment of colorectal cancer."

The cancer stem cell hypothesis holds that a fraction of the malignant cells in a tumor have characteristics associated with normal stem cells, namely the ability to self-renew and to give rise to other cell types. The hypothesis also holds that in order to successfully eliminate a tumor, the cancer stem cells must be eliminated as well; if they are not, they could serve as seeds for the tumor to regrow or spread.

"When the cancer stem cell concept was first posited, it was thought that the stem cell subset might coincide with the subset that remains after therapy and that metastasizes," Markus Frank said. "This subset has historically been a hidden target, because we have not been able to define and isolate it. But therapies capable of killing off those cells at the root of the cancer would be much more effective than those that miss this subset."

This work was supported by grants from the National Cancer Institute and the U.S. Department of Veterans Affairs.

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