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Combating resistance to radiation

$1.4M VA grant will help UC researcher study radiation resistance in patients with head and neck cancers

A University of Cincinnati cancer researcher received a $1.4 million federal grant to study radiation resistance in head and neck cancer and ways to target molecular pathways in patients to make this form of treatment more effective.

The five-year U.S. Department of Veterans Affairs (VA) Career Development Award will help principal investigator Vinita Takiar, MD, PhD, assistant professor of radiation oncology at the UC College of Medicine and a UC Health radiation oncologist, examine this problem in veterans.

“Head and neck cancer is the sixth most common cancer worldwide and is diagnosed twice as frequently in veterans. Unlike other sites of the body, where cancers can be removed surgically, the head and neck is a difficult area in which to operate, and there is not as much that can be removed before there is functional impairment for the patient,” she says. “Radiation is a good option in certain cases, and there are clear benefits to radiating the tissue to prevent disease recurrence, even after surgery. However, even after high doses of radiation, which cause significant side effects to the patient, the tumor can reappear within the treated area. We want to understand how this happens and then target those pathways to make radiation more effective.”

This research will lay the groundwork for future clinical trials and is expected to identify additional unknown, yet effective treatment combinations (for head and neck cancer).

Vinita Takiar, MD, PhD

Takiar, also a member of the UC Cancer Institute, says the study will use Reverse Phase Protein Arrays (RPPA), a protein microarray tool, to strategically identify and compare treatment combinations that could target various molecular pathways and combat therapy resistance. The use of RPPA to identify new therapies to be used in combination with radiation has not been investigated previously.

“This study will hopefully help us combine newly identified targeted treatments with radiation therapy to result in maximum treatment efficacy while minimizing side effects,” she says, noting that nearly all patients who currently get a combination therapy have limited options, with most getting cisplatin, a type of chemotherapy. “We will start by looking at the combination of radiation therapy with a glutaminase inhibitor, known as CB-839, to see if it makes cancer cells in culture more likely to die from radiation.”

Vinita Takiar holding a dish in the laboratory

Vinita Takiar, MD, PhD. Photo Credit: Colleen Kelley / Communication Services

By blocking glutaminase, a derivative of glutamine (an amino acid used in the biosynthesis of proteins), the energy producing machinery of cells becomes impaired, making it harder for cells that are damaged by radiation to repair themselves and continue to survive.

Takiar adds that researchers will validate the efficacy of glutaminase inhibition by testing it alone and in combination with radiation therapy. She and her team will also work to identify other new head and neck cancer cellular pathways that are altered by radiation therapy using samples taken from patients, treating them with radiation and then looking at their molecular changes.

“This research will lay the groundwork for future clinical trials and is expected to identify additional unknown, yet effective treatment combinations,” she says. “The treatment of head and neck cancers in the VA population deserves special consideration because of the patient population’s risk factors, overall outcomes and cost of their care. We hope this study will lead to more effective treatment for veterans with head and neck cancers and eventually help others with the disease.”

Featured Photo: Vinita Takiar, MD, PhD. Photo Credit: Colleen Kelley / Communication Services 

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UC researchers say early puberty in girls may be the new big...

Wed, July 10, 2019

CINCINNATI—Adolescent girls who reach puberty at an earlier age may also have a greater chance of developing migraine headaches, according to new research from investigators at the University of Cincinnati (UC) College of Medicine. “We know that the percentage of girls and boys who have migraine is pretty much the same until menstruation begins,” says Vincent Martin, MD, professor in the Division of General Internal Medicine and director of the Headache and Facial Pain Center at the UC Gardner Neuroscience Institute. “When the menstrual period starts in girls, the prevalence goes way up, but what our data suggests is that it occurs even before that.” The findings will be presented by Martin at the American Headache Society 61st Annual Scientific Meeting Saturday, July 13, in Philadelphia. Nationally, about 10 percent of school age children suffer from migraine, according to the Migraine Research Foundation (MRF). As adolescence approaches, the incidence of migraine increases rapidly in girls, and by age 17, about 8 percent of boys and 23 percent of girls have experienced migraine, the MRF reports. Martin and a team of researchers were part of a longitudinal study looking at 761 adolescent girls from sites in Cincinnati, New York and the San Francisco Bay area. The girls ranged in age from 8 to 20 and study took place over a 10-year period beginning in 2004. Girls enrolled in the study at age 8-10 were examined during study visit every six to 12 months. Researchers determined when they showed initial signs of thelarche (breast development), pubarche (pubic hair growth) and menarche (start of menstrual periods). Girls answered a headache questionnaire to find out if they suffered from migraine headache, no migraine or probable migraine—the latter is defined as meeting all the diagnostic criteria for migraine except one. The average age at which they completed the survey was 16. Of those surveyed, 85 girls (11 percent) were diagnosed with migraine headache while 53 (7 percent) had probable migraine and 623 (82 percent) had no migraine, according to Martin, also a UC Health physician specializing in migraine. Researchers found that girls with migraine had an earlier age of thelarche (breast development) and the onset of menarche (menstrual periods) than those with no migraine. On average breast development occurred four months earlier in those with migraine while menstruation started five months earlier. There was no difference in the age of pubarche (pubic hair development) between those with migraine and no migraine. “There was a 25 percent increase in the chance of having migraine for each year earlier that a girl experienced either thelarche or menarche,” says Susan Pinney, PhD, professor in the UC Department of Environmental Health and lead investigator on the study. “This suggests a strong relationship between early puberty and the development of migraine in adolescent girls.” The age of onset of thelarche, pubarche or menarche did not differ between those with probable migraine and no migraine, says Pinney. Previous research suggests that migraine often starts with the onset of menstrual cycles during menarche in adolescent girls. But this study looks at earlier stages of puberty such as thelarche and pubarche, explains Martin. “To suggest the origins of migraine may occur actually before menstrual periods begin is pretty novel,” says Martin. “At each of these stages, different hormones are starting to appear in girls. During pubarche, testosterone and androgens are present, and during thelarche, there is the very first exposure to estrogen. Menarche is when a more mature hormonal pattern emerges. Our study implies that the very first exposure to estrogen could be the starting point for migraine in some adolescent girls. It may be the Big Bang Theory of migraine.” So is there anything that one can do to prevent an early puberty? “Studies suggest that childhood obesity is associated with early puberty,” says Martin, who is also president of the National Headache Foundation. “Keeping your weight down might prevent the early onset of puberty. Future studies will need to be done to determine if strategy will decrease also the likelihood of developing migraine.” Other co-investigators in the study include Frank Biro, MD, UC professor in the Department of Pediatrics and Cincinnati Children’s pediatrician, Jun Ying, PhD, professor in the UC Department of Environmental Health, and Hao Yu, biostatistician, UC Department of Environmental Health. Funding for this research came grant U01ES026119 from the National Institute of Environmental Health Sciences and grant 1R03HD094236 of the Eunice Kennedy Shriver National Institute of Child Health and Human Development.

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