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Research and Advances

Tumor Resistance to Chemotherapy

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Chemotherapy and radiation therapy are the common post-surgical treatments for cancerous tumors. They are designed to kill any cancer cells that were not removed during surgery, while allowing normal cells to survive.

Unfortunately, some tumors resist therapy, sometimes better than the body’s normal cells. The result is that the tumor cells do not die and the tumor continues growing.

Seattle Children’s Hospital has several research teams investigating new ways to successfully treat tumors, including how tumors respond to and resist therapy, and developing strategies and therapies to improve clinical outcomes.

Background on Tumors and Tumor Treatment

Tumors that originate in the brain happen in 40,000 Americans every year, with about 3,000 of them occurring in children. Brain tumors and leukemia are the most common childhood cancers that we treat at Seattle Children’s.

Gliomas

About 75% of childhood brain tumors are gliomas. Gliomas in children include the astroglial types found in adults as well as ependymoma tumors and neuronal glial tumors.

About 20% of childhood gliomas are in the cerebellum. Adults rarely develop tumors in this part of the brain.

More than 75% of childhood cerebellar gliomas are pilocytic astrocytomas. We can usually treat these low-grade tumors with surgery. After surgically removing the whole tumor, the five-year survival rate is 95%.

Medulloblastomas and primitive neuroectodermal tumors (PNETs)

Medulloblastoma and the primitive neuroectodermal tumor (PNET) are highly malignant cancers. They make up 20 to 25% of the primary brain tumors diagnosed in children each year in the United States.

Medulloblastomas and PNETs are identical in cellular appearance. We tell them apart mostly by where they are in the body: medulloblastomas happen in the cerebellum while PNETs happen almost exclusively in the cerebral hemispheres.

The good news is that advances in chemotherapy and radiation therapy have made medulloblastomas more treatable. Current post-surgery treatments work well for many children. The outcome for PNETs is still poor.

Some diagnostic and treatment statistics regarding medulloblastomas and PNETs:

  • The median age at diagnosis is approximately 9 years.
  • Sixty-two percent of these tumors occur in males.
  • Rarely, medulloblastomas and PNETs happen in adults between 20 and 40 years of age.
  • The overall five-year survival rate ranges from 60 to 85 percent for children with a medulloblastoma who have surgery to remove their tumor and follow up with both radiation therapy and chemotherapy.
  • The outlook is worse for the 10 to 30% of patients whose cancer has spread throughout their brain and entire spine at the time they are diagnosed.
  • PNETs spread more quickly and respond less well to treatment than tumors in the cerebellum. Children with PNETs have a five-year survival rate of less than 20%.

Post-Surgery Treatment for Gliomas and Medulloblastomas

Improved surgical methods often make it possible for our neurosurgeons to remove most of a tumor. This is very helpful for post-surgery treatment.

Post-surgical treatment for malignant (cancerous) gliomas and high-risk medulloblastomas usually includes targeted radiation therapy and systemic chemotherapy, which travels throughout the entire body.

However, some of the newer therapies being studied limit chemotherapy to the central nervous system. For example, after removing the tumor, neurosurgeons implant gliadel wafers, which contain the chemotherapy drug Carmustine (BCNU), where the tumor used to be.

The disease-free survival rate improves for children who receive radiation therapy and chemotherapy. The sensitivity of the child’s tumor cells affects how well the therapy works.
So does the size of the tumor when it is treated. Sometimes, a small percentage of the tumor’s cancer cells resist therapy.

Therapies are meant to increase survival rates and improve a child’s short- and long-term quality of life. The research team directs their research at improving quality of life without reducing the effectiveness of cancer treatments.

Treatment Limitations

Advances in medical radiation therapy, chemotherapy and surgical treatments have greatly increased the chances of surviving a malignant brain tumor.

However, radiation therapy and chemotherapy can have disappointing results when used to treat many childhood brain tumors, based on several factors:

  • The tumor’s cellular or biological make-up
  • The tumor’s location
  • The child’s age
  • Limitations caused by the basic biology of childhood brain tumors and nearby normal brain tissue

Questions and Answers with Michael Bobola, PhD

 

bobola
Michael Bobola, PhD

 

Q: Why are you trying to improve treatments for brain tumors?

A: There are several reasons. There is no treatment that produces long-term remission in more aggressive (high-grade) tumors that come back. Remission means the tumor is either gone or shrinking, yet the child can still have seizures or other clinical symptoms.

We can lessen symptoms with medicine but the tumor will likely grow back.

In addition, radiation therapy has long-term effects on the physical and mental development of infants and young children.

Also, in very young children, chemotherapy takes a major role in treating brain tumors and has a risk of side effects.

Q: What is the focus of your research?

A: We are working in several treatment areas including the following:

Assessing the relationship between a cell’s ability to repair its DNA and a tumor’s response to therapy

Many cancer treatments target the DNA in the tumor cells. The treatment keeps the cells from dividing or growing, so they die. Our research is working toward taking advantage of this in treating tumors.

Our goal is to decrease a cancer cell’s ability to repair its DNA, while still allowing normal cells to repair themselves. In other words, we’re working to create a switch that says to the cancer cells, “You’ve been damaged. Now, don’t repair yourself. Die.”

Collecting tissue from the operating room to use in developing molecular biochemical profiles

Molecular biochemical profiles will help us learn how a specific therapy will affect a tumor and the rest of the child’s body. In the future, we hope to use molecular profiling of a tumor to custom design therapies for each patient. More research is needed to get to this point.

Developing techniques to change repair activity in a test tube (in vitro)

This will help us evaluate how cancer cells survive treatment. Then, we can develop better therapies to counter the resistance of the cancer cells.

Developing techniques that alter repair activities in living tissue (in vivo)

This will help us improve the effectiveness of DNA-damaging-based therapies.

Developing new treatment plans

This includes understanding, before therapy begins, how a tumor will respond to the treatment, and then developing protocols (standard plans) that prevent tumors from returning. It also involves combining new and older chemotherapy and radiation therapy to make the most of cellular response to DNA damage.

Also, combining new and older chemotherapy and radiation therapy to make the most of cellular response to DNA damage.

Q: How will your team’s findings benefit children who have brain tumors?

A: Our findings will increase the effectiveness of radiation therapy and chemotherapy. Along with surgical advances, improved non-surgical treatments may increase the likelihood of successfully treating children who have brain tumors.

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