Bench to Bedside

From Bench to Bedside

Getting the best new treatments to patients

lab photoFrom bench to bedside is a concept that most all medical discoveries are based on. Physician researchers find new treatments in the laboratory and through clinical trials, bring them to patients.

Dr. Robert Rostomily, a leading neurosurgeon at University of Washington Medical Center, is conducting research with the Institute for Stem Cell & Regenerative Medicine that will have a direct effect on the patients he treats for glioblastoma tumors in the future.

From his research, Rostomily is learning how glioma cells invade the body to cause cancer metastasis. Epithelial to Mesenchymal transition (EMT for short) is the medical name for is an invasion process that has been linked to cancer stem cell activity in gliomas. Glioma cancer stem cells may thus be important both for tumor growth and metastasis.

“Understanding this process [cancer stem cell growth] will help us target treatments better,” Rostomily says. “The key regulatory function in gliomas may affect broader types of cancer, too. If we can target one, it may have a broader affect on treatment resistance in general.”

Brain cancers are difficult to treat. Stem cells are considered to be related to the underlying resistance for initial therapy. If cancer stem cells are resistant to treatment, the tumor may keep growing.

Stem cells and brain cancer

“Stem cells are a therapeutic delivery system,” Rostomily says. It’s figuring out how to get stem cells to do the work in treatment that will be the key to better patient outcomes.

Dr. Hans-Peter Kiem is investigating using bone marrow (stem cell) transplants, with “protected stem cells,” for treating solid tumors, specifically glioblastoma.

“The concept is straightforward,” he says. “We’ve worked in the lab to make [bone marrow] stem cells resistant to chemotherapy. One of the genes we’ve been using makes [bone marrow] stem cells resistant to the key chemotherapies used for glioblastoma (GBM).”

In general, when certain chemotherapy drugs are used, GBM patients become neutropenic and their counts become too low to deliver enough chemotherapy to treat the cancer.  The idea from Kiem’s lab is to perform a non-myeloablative bone marrow transplant, give patients stem cells that have been pre-protected with the resistance gene, and then treat the cancer with more doses of chemotherapy than can be used otherwise. Patients become neutropenic, low number of neutrophils (type of white blood cell),  for only a couple days and the entire treatment is done on an out-patient basis.

“The patient can then receive more chemotherapy drugs than is typically possible to treat their cancer, which will result in better treatment and survival,” Kiem says.

There have been three patients on this trial already. Two are still on the study and one is now off of the study. “We are continuing chemotherapy longer in these patients than in any other study currently,” Kiem says. After they receive their transplant at SCCA, each patient is sent back to their neuro-oncologist.

“Time will tell if this will result in better outcomes, but we are very happy with results,” he says. “We’ve had very good stem cell engraftment of these chemo-protective cells.”

DNA and targeted therapies

Dr. John Silber, a researcher at the University of Washington, is studying the effects of cancer treatment on DNA and how to go about repairing damaged DNA. Once altered, he says, DNA becomes resistant to further treatment. Silber is also interested in targeting treatment to avoid affecting healthy, non-cancerous cells and looks to scorpion venom and nanotechnology for answers.

“In the last 20 years, we’ve come to understand that DNA repair promotes resistance to radiation and/or drugs with brain tumors,” Dr. Silber says.

Chemotherapy drugs and radiation kill cells and alter DNA. “If the DNA isn’t repaired,” he says, “then DNA duplication comes to a halt (thus killing the cancer cell). We are looking at the whole cell and the genes and identifying them. In the lab we measure DNA, and repair new tumors removed in surgery. We follow the clinical course of patients to see how long it takes before a recurrence. Is there any association between DNA repair activity of a cancer cell to the time of recurrence?” Silber asks. There are at least 100 ways a tumor can be resistant to treatment. Silber says they have a long way to go to find the answer because they’ll need to measure thousands of tumors.

But there is one drug now being used that is showing promise today called Temozolomide. Given in low doses before radiotherapy, this drug seems to improve patient outcomes because Temozolomide interrupts DNA replication.

“It takes hours to recover. Radiation damages DNA with free radicals the drug enhances radiosensitivity,” Silber says. “What’s the mechanism of action? How does this work at a molecular level? And, why does the drug and radiation therapy together work better than alone? We know we can increase tumor response two-fold. Why? What’s the common theme?” Silber is working to find that answer, too.

Targeting treatment

But he’s also interested in getting more treatment into tumors instead of healthy cells. One way to target treatment may be using scorpion venom molecules because they can identify brain tumor glioblastoma cells. Another answer may be nanotechnology. There are nano particles that have been developed that cross the blood-brain barrier in animal models. Nanotechnology can help get drugs like Temozolomide to brain tumors over the blood-brain barrier.

We will move to Proof-of-Purpose experiments and then animal studies eventually,” Silber says, though it will be quite a while before it’s ready for use in humans.

From bench to bedside, these physician researchers are working to put new medical discoveries into action to eventually become tomorrow’s treatment for patients.

For more information about Translational Research, contact Sandra Johnston, PhD, RN, researcher, at (206) 288-6365.