Last week we mentioned a lecture Dr. Kristiina Vuori, Sanford-Burnham’s president and director of our NCI-Designated Cancer Center, gave to San Diego’s CONNECTcommunity about the Institute’s many exciting advances in cancer research.So how exactly do Sanford-Burnham researchers put cancer cells in their place?
As Dr. Vuori highlighted in her lecture, scientists in each of Sanford-Burnham Cancer Center’s four programs – Tumor Development, Signal Transduction, Tumor Microenvironment and Apoptosis and Cell Death Research – are designing new therapies that tackle cancer during every step of the disease’s progression. Here are just a few examples of Sanford-Burnham’s multi-pronged approach, as described by Dr. Vuori…
Step 1: Something goes wrong in a cell
Cancer stem cells are a hot area of focus in the Cancer Center’s Tumor Development Program. Some scientists believe that a single cancer stem cell may be the culprit behind tumor formation. Much like other types of tissue stem cells, cancer stem cells can give rise to a variety of cell types. Thus, scientists at Sanford-Burnham and elsewhere are beginning to think that many cancers are caused by a small population of “initiator” stem cells in adult tissue, which gives rise to all the other cells in the tumor. This notion has led to the belief that while many current treatments (such as chemotherapy or radiation therapy) destroy the majority of the tumor cells, it only takes a few remaining cancer stem cells to re-initiate the tumor. Luckily, these cancer stem cells have certain molecular characteristics that make them distinguishable from other cells.
Researchers in the Tumor Development Program are now finding ways to distinguish cancer stem cells from other tumor cells and using this information to design treatments that specifically kill them without harming other tissues. Collaboration between two Sanford-Burnham laboratories has led to the discovery that an enzyme called MELK could be a potential marker for early tumor development.
Step 2: Cancer cell growth spins out of control
Cancer is rarely detected in the early stages. Cancer cells eventually become a large tumor mass often because cellular signals that are supposed to regulate growth aren’t working properly. Cells are supposed to receive information from their surroundings through receptors on the cell surface. The signal then passes into cells, triggering events that control and regulate cell growth. Cancer cells, however, ignore these environmental signals and keep growing even while the body tries to control the growth. Sanford-Burnham’s Signal Transduction Program studies how these regulatory mechanisms go wrong in cancer. Here, two groups are studying EphA2, a cell signaling receptor found on the surface of cancer cells but not in most normal cells. In one approach, researchers are now working with pharmaceutical companies to look for drugs that inhibit EphA2, which is an enzyme that affects cellular function by adding phosphate groups to other proteins. In another approach, they are also using the knowledge that EphA2 is only expressed in cancer cells to team up cell-destroying drugs with molecules that specifically bind to the receptor, killing cancer cells while leaving normal cells untouched.
Step 3: Tumors metastasize
In later stages of cancer, tumors are no longer isolated clusters of cells. They direct the construction of new blood vessels that bring fresh oxygen and nutrients to the growing mass – a process known as angiogenesis. These new roadways also connect the tumor to the body’s circulatory system, providing cancer cells with a means of escape. In Sanford-Burnham’s Tumor Microenvironment Program, scientists are trying to determine what allows some cancer cells to metastasize. Scientists are looking for ways to choke off the blood supply and block their escape. What’s more, some researchers at Sanford-Burnham are also targeting cells that have already left the nest. One group is developing short proteins called CendR that specifically home in on both cancer cells and the blood vessels that feed them. CendR and similar technologies are being coupled with known anti-cancer drugs such as Herceptin® (currently prescribed to treat certain kinds of metastatic breast cancer) to dramatically increase their potency and minimize side effects.
Step 4: Cancer cells resist treatment
Regardless of how well anti-cancer drugs work at the beginning, there are almost always some cancers that manage to keep coming back. Cancer cells can learn to resist death imposed by radiation, chemotherapy or other drugs by changing their genes or altering expression of proteins on the cell surface. But the main reason some cells are able to resist treatment is because they can prevent activation of the programmed cell death pathway, called apoptosis. Most cancer drugs work by inducing stress in the cell, which results in molecules leaking out of the mitochondria (the part of the cell that generates energy) and activating enzymes known as caspases. Activation of caspases then leads to irreversible cell damage and apoptosis. Since cancer cells survive by activating caspase inhibitors called IAP proteins, Sanford-Burnham scientists in the Apoptosis and Cell Death Research Program are trying to trick cancer cells into committing suicide by taking IAPs away and allowing apoptosis to proceed.
Some groups are also tackling Bcl-2 proteins, a family of mitochondrial proteins that antagonize one another to drive either cellular survival or death. Cancer cells have more pro-survival Bcl-2 proteins than normal cells do. Sanford-Burnham scientists have already developed drugs that shift the balance of pro-death and pro-survival Bcl-2 members to wipe out cancer cells and are continuing to improve them.
For more about Dr. Vuori’s CONNECT lecture, read Tumors Beware, Part I.