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From OncoLog, August 2013, Vol. 58, No. 8

Targeted Cancer Therapies May Help Overcome Resistance to Radiation Therapy

By Sarah Bronson

Some cancer cells are resilient enough to withstand and recover from the damage to their DNA caused by radiation therapy. But recent studies have shown that adding molecularly targeted agents to radiation therapy can prevent the repair of this radiation-induced damage and thereby improve the treatment response of patients with certain cancers.  

Stronger, more durable responses

Although radiation is intended to destroy cancer cells by damaging their DNA, the DNA often can be repaired, resulting in only temporary responses to treatment. In some cases, radiation can actually increase the expression of cancer-driving genes such as the epidermal growth factor receptor (EGFR), resulting in radiation resistance. However, drugs that inhibit proteins central to cancer growth or DNA repair, such as the EGFR inhibitor cetuximab, can impede DNA repair and make cancer more susceptible to radiation.

Photo: Dr. James Welsh
“Radiation that damages DNA can be combined with a targeted drug that blocks the repair of that DNA.”

– Dr. James Welsh

“Radiation that damages DNA can be combined with a targeted drug that blocks the repair of that DNA,” said James Welsh, M.D., an assistant professor in the Department of Radiation Oncology at The University of Texas MD Anderson Cancer Center, who has led several studies in which targeted drugs were used to overcome radioresistance in cancer. Indeed, adding cetuximab to radiation therapy has been shown to prolong overall survival in patients with head and neck cancer.

According to preclinical studies, inhibitors of PARP1 (a protein involved in repairing DNA damage) also have the potential to selectively radiosensitize cancer cells. Clinical trials of the PARP1 inhibitor veliparib in combination with radiation therapy to treat various cancers are being planned or are under way at MD Anderson and elsewhere.

Another potential therapeutic target is the hepatocyte growth factor receptor c-Met, which enables cellular invasion. In a recent study, non–small cell lung cancer cells in which previous radiation had induced higher c-Met expression levels were radiosensitized by the c-Met inhibitor MK-8033.

Radiosensitizing therapies can be particularly valuable when a tumor’s proximity to sensitive structures, such as the esophagus, aorta, or brain, makes it difficult to use high doses of radiation. Dr. Welsh said, “To avoid unnecessary damage, you can use a biological approach to specifically sensitize tumor cells and increase the efficacy of radiation without increasing the toxicity to normal cells.”

With targeted agents, the ratio between the benefit from therapy and the severity of potential side effects (i.e., the therapeutic ratio) is increased. In a recent study led by Dr. Welsh, selected patients with brain metastases from non–small cell lung cancer benefited from treatment with the EGFR inhibitor erlotinib combined with radiation. Erlotinib (a small molecule capable of crossing the blood-brain barrier) impedes DNA repair, antiapoptotic pathways, and proliferation. Adding erlotinib to whole-brain radiation therapy in patients with brain metastases led to a median overall survival of 11.8 months, which was a significant improvement over the median overall survival of 3.9–6.0 months for historical controls. In both treatment groups, patients with EGFR gene mutations had a significantly longer median survival time than did patients without such mutations.

Dr. Welsh said that even within the same type of cancer, those tumors with certain gene mutations are more susceptible than others to treatment with targeted drugs plus radiation; in fact, many such treatments are effective only against cancers with specific mutations. But with recent advances in gene sequencing technology, researchers are identifying more and more targetable mutations that may identify cancers that are suitable for this type of combination treatment.

Dr. Welsh also noted that using targeted therapy to sensitize cancer to radiation and improve the response to radiation might make radiation therapy more effective in parts of the world where the latest technology is unavailable. “Radiation is an expensive technology,” he said. “The equipment and expertise for precisely targeted delivery systems such as proton therapy or intensity-modulated radiation therapy are often not available or affordable, especially in less developed countries. But if we add biological therapy to radiation, we might be able to improve the outcomes from standard radiation therapy techniques.”

Potential for distant control

In a very small number of cases, radiation combined with monoclonal antibodies or other immunotherapies has achieved not only locoregional control but also distant, systemic control of advanced cancer by exploiting the immune system. Through a phenomenon called the abscopal effect, radiation induces antigens specific to cancer cells, priming T cells to attack cancer cells outside the radiation field.

Photo: Dr. Lauren Byers
“We’re testing the impact of hitting different places along the pathway of DNA repair in cancer cells.”

– Dr. Lauren Byers

Immunotherapy agents counter the mechanisms by which cancer cells typically protect themselves from the host’s immune system, rendering cancer cells throughout the body vulnerable to the tumor-specific T cells. Thus, in a patient with advanced disease, both the primary tumor and the metastases may respond to local irradiation of the primary tumor combined with immunotherapy.

The abscopal effect has been observed in isolated cases of melanoma, lymphoma, and kidney cancer. For example, in a few case reports of patients with metastatic melanoma, treatment with ipilimumab and stereotactic radiation not only reduced the irradiated tumor but also led to reductions in the nonirradiated tumors.

Dr. Welsh said that the abscopal effect may also yield more durable responses than cytotoxic therapy alone. “A better understanding of this type of response could lead to a future with less dependency on chemotherapy,” Dr. Welsh said. “Once T cells are primed to attack a particular cancer cell, they stay in the body and could potentially vaccinate a patient against new cancer cells.”

Lauren Byers, M.D., an assistant professor in the Department of Thoracic/Head and Neck Medical Oncology, added that immunotherapy is also being investigated in combination with growth pathway–targeting drugs to help the immune system recognize and attack cancer cells. On the whole, cancer cell–seeking therapy has the potential to benefit patients whose cancers are resistant to radiation therapy or other treatments.

Patient selection

Targeted therapy combined with radiation therapy is being explored for patients whose cancers have a recognized gene mutation or aberrant protein for which a targeted drug is available. Many targeted drugs now exist; however, some have yet to be studied in combination with radiation.

Furthermore, enrolling a sufficient number of patients with the appropriate mutations in trials of targeted drugs with radiation therapy can be difficult. In addition to finding patients with a condition such as brain metastases from lung cancer, researchers may need to study patients who meet more selective criteria—having metastases to the brain from an EGFR-mutant non–small cell lung cancer, for example. “It’s a subset of a subset of a subset,” Dr. Welsh said of a group of patients treated with an EGFR inhibitor and radiation in a recent trial.

Still, Dr. Byers said that the rapidly accelerating development of targeted drugs is leading to more personalized treatments for an ever-increasing proportion of cancer patients. Using lung cancer as an example, she said, “Right now, about 20% of lung cancers have mutations that can be targeted by approved drugs. For some of the newer drugs, such as RET and BRAF inhibitors, we don’t have a full picture of how many patients with those mutations will benefit, but trials are under way to fill in those gaps. It won’t be long until targeted drugs for many more mutations in many types of cancer are available, and some of these drugs will likely enhance radiation therapy.”

New targets

New classes of drugs are rapidly being developed to target tumor cell and blood vessel growth, DNA repair, and other processes critical to cancer growth and spread. As more therapeutic targets are identified, more combinations of targeted drugs with radiation therapy will become available in trials. “Groups of proteins work together to orchestrate DNA repair, and we’re testing the impact of hitting different places along the pathway of DNA repair in cancer cells,” Dr. Byers said.

“You can use a biological approach to specifically sensitize tumor cells and increase the efficacy of radiation without increasing the toxicity to normal cells.”

– Dr. James Welsh

Matching treatments to a patient’s cancer at the molecular level also opens up new uses for existing drugs that have typically been used to treat only one or a few specific cancers. For example, trastuzumab, a monoclonal antibody used in the treatment of breast cancer to block the HER2 cell surface receptor, may also improve outcomes from radiation therapy in some patients with esophageal cancer.

However, the many treatment possibilities presented by targeted drugs need to be narrowed down to effective, safe treatment strategies. Key targets for specific cancers need to be validated in clinical trials of new targeted drugs given individually and in combination with radiation, chemotherapy, or other targeted drugs. The schedules on which different treatment modalities should be given need to be determined—whether a drug should be given before or after radiation, for instance.

Another concern to be addressed by researchers is that drugs combined with radiation may give rise to complications that do not occur with either treatment alone (e.g., tracheal-esophageal fistula from bevacizumab with radiation).

“It’s a very exciting time because of all the new targets that are out and all the new data we’re getting on patients’ tumors,” Dr. Welsh said. “But figuring out how to use these drugs properly is a challenge we need to undertake methodically with organized studies so that we can learn how to do this in a safe and effective manner.”

FURTHER READING

Bonner JA, Harari PM, Giralt J, et al. Radiotherapy plus cetuximab for squamous cell carcinoma of the head and neck. N Engl J Med. 2006;354:567–578.

Bhardwaj V, Zhan Y, Cortez MA, et al. c-Met inhibitor MK-8033 radiosensitizes c-Met–expressing non–small cell lung cancer cells with radiation-induced c-Met expression. J Thor Oncol. 2012;7:1211–1217.

Welsh JW, Komaki R, Amini A, et al. Phase II trial of erlotinib plus concurrent whole-brain radiation therapy for patients with brain metastases from non–small cell lung cancer. J Clin Oncol. 2013;31:895–902. 

For more information, call Dr. James Welsh at 713-563-2447 or Dr. Lauren Byers at 713-792-6363.

Other articles in OncoLog, August 2013 issue:

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