Researchers find potential target for treating metastatic cancer

December 13, 2011

Finding ways to counteract or disrupt the invasive nature of cancer cells, called "metastasis," has been a long-term goal of cancer researchers. Now, researchers at Moffitt Cancer Center in Tampa, Fla., have identified an interactive pathway that regulates metastases in some cancers that may be vulnerable to chemical targeting in order to prevent cancer cell proliferation and tumor growth.

Ongoing collaboration by researchers in Moffitt's Departments of and has revealed the potential for combating metastatic disease by disrupting the interaction between the retinoblastoma (Rb) and Raf-1 (a gene with a potential to cause ) with RRD-251, a selective, chemical disrupter of Rb-Raf-1 interaction.

Their recent study, aimed at understanding the association between Rb-Raf-1 and genes known to be over-expressed in metastatic non-small lung cancer, was published in the recent issue of , a journal of the American Association for Cancer Research. This work, using a mouse model, was a continuation of the researchers' study of RRD-251's successful disruption of Rb-Raf-1 interaction in metastatic melanoma in test mice, a study published in Molecular Cancer Therapeutics in 2010.

"The Rb gene is mutated in a variety of cancers," said study corresponding author Srikumar P. Chellappan, Ph.D., chair of Moffitt's Department of Tumor Biology and scientific director of the National Functional Genomics Center. "Our earlier studies have shown that Raf-1 interacts with Rb early in the cell cycle and facilitates its inactivation."

The ongoing work of Chellappan and his colleagues in Moffitt's Department of Tumor Biology focuses on understanding the mechanisms by which external signals regulate cell proliferation and how a loss of regulation may cause cancer. They work extensively with the Rb protein, the Raf-1 signaling molecule, and E2Fs, genes that affect cell proliferation, differentiation and cell death (apoptosis).

E2Fs, a family of genes that play a role in the mammalian cell cycle and can transform normal cells to have properties of , interact with Rb. In addition, E2Fs are important for the development, differentiation and DNA damage repair programs in cells. Their previous studies have shown that RRD-251-mediated disruption of the Rb-Raf-1 interaction could inhibit the activity of E2F. They now show that E2Fs regulate matrix metalloproteinases (MMPs), which are involved in cancer metastasis, and RRD-251 can prevent the expression of MMPs.

"A considerable amount of research has been dedicated to identifying novel E2F- regulated genes, but a clear role for E2Fs in cancer progression and metastasis had not been established," explained Chellappan. "We find that the Rb-E2F pathway contributes to the expression of many genes involved in different aspects of cancer, and that targeting this pathway might fight metastatic disease."

Their study found that a mouse model of non small cell lung cancer metastasis being treated with RRD-251 had "significantly less metastasis to the lung and surrounding areas." They concluded that disrupting the Rb-Raf-1 interaction using RRD-251 could inhibit the regulatory function of E2Fs as an activator of gene promoters that are related to and metastases.

"There is a possibility that E2F might indirectly regulate tumor metastasis as a consequence of its activating these genes," suggested Chellappan. "Taken together, our studies link the Rb-E2F cell cycle regulatory pathway to advanced stages of cancer development and metastasis."

Although further studies are underway, their work suggests that disrupting Rb-Raf-1 interaction can prevent cancer , cell vascular growth (angiogenesis), tumor growth, and the metastatic colonization of organs.

"This approach appears to be a fruitful avenue to combat metastatic disease," concluded Chellappan.

Explore further: Protein boosts lung cancer in smokers, non-smokers; Potential anti-oncogenic target

Related Stories

Protein boosts lung cancer in smokers, non-smokers; Potential anti-oncogenic target

July 19, 2011
Lung cancer is strongly correlated with smoking, and most lung cancer patients are current or former smokers. But it is not rare in nonsmokers. Now, a team of researchers from the H. Lee Moffitt Cancer Center and Research ...

SABCS: Loss of RB in triple negative breast cancer associated with favorable clinical outcome

December 9, 2011
Researchers at the Thomas Jefferson University Hospital and Kimmel Cancer Center at Jefferson have shown that loss of the retinoblastoma tumor suppressor gene (RB) in triple negative breast cancer patients is associated with ...

Recommended for you

Lung cancer triggers pulmonary hypertension

November 17, 2017
Shortness of breath and respiratory distress often increase the suffering of advanced-stage lung cancer patients. These symptoms can be triggered by pulmonary hypertension, as scientists at the Max Planck Institute for Heart ...

Researchers discover an Achilles heel in a lethal leukemia

November 16, 2017
Researchers have discovered how a linkage between two proteins in acute myeloid leukemia enables cancer cells to resist chemotherapy and showed that disrupting the linkage could render the cells vulnerable to treatment. St. ...

Computer program finds new uses for old drugs

November 16, 2017
Researchers at the Case Comprehensive Cancer Center at Case Western Reserve University School of Medicine have developed a computer program to find new indications for old drugs. The computer program, called DrugPredict, ...

Pharmacoscopy improves therapy for relapsed blood cancer in a first clinical trial

November 16, 2017
Researchers at CeMM and the Medical University of Vienna presented a preliminary report in The Lancet Hematology on the clinical impact of an integrated ex vivo approach called pharmacoscopy. The procedures measure single-cell ...

Wider sampling of tumor tissues may guide drug choice, improve outcomes

November 15, 2017
A new study focused on describing genetic variations within a primary tumor, differences between the primary and a metastatic branch of that tumor, and additional diversity found in tumor DNA in the blood stream could help ...

A new strategy for prevention of liver cancer development

November 14, 2017
Primary liver cancer is now the second leading cause of cancer-related death worldwide, and its incidences and mortality are increasing rapidly in the United Stated. In late stages of the malignancy, there are no effective ...

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.