Cancer researchers led by scientists at Beth Israel Deaconess Medical Center identify a previously unrecognized problem faced by mTOR inhibitors, shining a light on the MAPK pathway.

Nearly a decade ago, while it was being tested as an immunosuppressive agent to prevent organ rejection in transplant patients, the drug rapamycin was also discovered to have anti-tumor properties. Since then, several rapamycin analogs known as mTOR (mammalian target of rapamycin) inhibitors have been tested in clinical trials for the treatment of various types of cancer. But despite promising early results, mTOR inhibitors have proven less successful than originally expected.

Now research led by scientists at Beth Israel Deaconess Medical Center (BIDMC) identifies a previously unrecognized problem faced by these agents when it comes to attacking cancers. Reported in the August 21 , 2008 advance on-line issue of The Journal of Clinical Investigation (JCI), the new findings show that at the same time that rapamycin analogs are halting tumor growth by inhibiting the mTOR protein complex 1 (mTORC1), they are activating the MAPK (mitogen-activated protein kinase) pathway -- thereby encouraging cancer cell survival.

“Anticancer research is aimed at understanding the molecular pathways that can be selectively targeted to halt tumor growth,” explains senior author Pier Paolo Pandolfi, MD, PhD, Director of Basic Research of the Cancer Center at BIDMC and Professor of Medicine at Harvard Medical School. “We know that the mTOR pathway is activated in many cancers, and therefore, is a good target for fighting a wide array of tumors.”

The mTOR pathway controls cell growth and angiogenesis through a series of mechanisms that integrate signaling from nutrients and other growth-promoting pathways. Activation of mTOR, therefore, promotes the proliferation of tumor cells, while inhibition of mTOR counters this action. However, because the mTOR signaling pathway is extremely complex, scientists have focused their efforts on identifying other agents that could be successfully combined with mTOR inhibitors to halt cancer growth.

From there, Carracedo and his coauthors went on to test a group of MAPK inhibitor agents to find out if, in combination with mTOR inhibitors, the agents would act to counter any pro-survival activity. And they did.

“This study inserts a new piece of information into the puzzle of the effects of mTORC1 inhibitors in cell signaling,” says Pandolfi. “Furthermore, because there are inhibitors of MAPK pathway already approved for the treatment of cancer, it provides us with the rationale for using combinations of mTORC1 and MAPK inhibitors in attacking tumors, thereby offering cancer patients another treatment option with immediate applicability.”

In addition to Pandolfi and Carracedo, study coauthors include BIDMC investigators Leonardo Salmena, Andrea Alimonti, Ainara Egia, Atsuo Sasaki, Antonella Papa, Caterina Nardella and Lewis Cantley; Memorial Sloan-Kettering Cancer Center investigator Julie Teruya-Feldstein in New York; Li Ma currently in the Whitehead Institute for Biomedical Research, Cambridge; George Thomas and Sara Kozma of the University of Cincinnati; and Federico Rojo and Jose Baselga from Vall d’Hebron University Hospital in Barcelona, Spain.

This work was supported, in part, by grants from the National Institutes of Health.

About Cancer

Cancer (medical term: malignant neoplasm) is actually a group of over 100 related diseases in which a group of cells display uncontrolled growth (division beyond the normal limits), invasion (intrusion on and destruction of adjacent tissues), and sometimes metastasis (spread to other locations in the body via lymph or blood). These three malignant properties of cancers differentiate them from benign tumors, which are self-limited, do not invade or metastasize. Most cancers form a tumor but some, like leukemia, do not. The branch of medicine concerned with the study, diagnosis, treatment, and prevention of cancer is oncology.

Sometimes cancer cells break away from the original tumor and travel to other areas of the body, where they keep growing and can go on to form new tumors. This is how cancer spreads. The spread of a tumor to a new place in the body is called metastasis (say: meh-tas-tuh-sis).

Cancer may affect people at all ages, even fetuses, but the risk for most varieties increases with age. Cancer causes about 13% of all deaths. According to the American Cancer Society, 7.6 million people died from cancer in the world during 2007. Cancers can affect all animals.

Nearly all cancers are caused by abnormalities in the genetic material of the transformed cells. These abnormalities may be due to the effects of carcinogens, such as tobacco smoke, radiation, chemicals, or infectious agents. Other cancer-promoting genetic abnormalities may be randomly acquired through errors in DNA replication, or are inherited, and thus present in all cells from birth. The heritability of cancers are usually affected by complex interactions between carcinogens and the host's genome. New aspects of the genetics of cancer pathogenesis, such as DNA methylation, and microRNAs are increasingly recognized as important.

Most cancers are named for the organ or type of cell in which they start - for example, cancer that begins in the colon is called colon cancer; cancer that begins in basal cells of the skin is called basal cell carcinoma.

Cancer types can be grouped into broader categories. The main categories of cancer include:

• Carcinoma - a cancer which is derived from the lining cells, or epithelium, of an organ. There are 4 major types of epithelium in the body (Glandular, squamous, transitional, and pseudostratified). Some types are only found in a few select organs such as the lung (pseudostratified) or urinary bladder (transitional).  Carcinomas can arise from any of these epithelial types. For example, breast carcinoma is most commonly derived from the lining cells of the milk producing glands. A carcinoma with a glandular growth pattern is an adenocarcinoma.  Common adenocarcinomas include prostate, colon, and breast.  A carcinoma with a growth pattern resembling the squamous lining cells is termed a squamous cell carcinoma.  Common squamous cell carcinomas are found in the esophagus and skin.  However, any of these organs may have either type of carcinoma arising from it, although these latter diagnoses are exceedingly rare.
• Central nervous system cancers - cancers that begin in the tissues of the brain and spinal cord.
• Leukemia - cancer that starts in blood-forming tissue such as the bone marrow and causes large numbers of abnormal blood cells to be produced and enter the blood.
• Lymphoma - a cancer derived from the white blood cells that are present in the lymphoid tissues of the body.  These sites most commonly include the lymph nodes and spleen. However, lymphomas may arise from any organ and body site.
• Sarcoma - cancer that begins in bone, cartilage, fat, muscle, blood vessels, or other connective or supportive tissue.