The generous members of City of Hope’s Circle 1500 are using the power of pooled philanthropy to improve prevention, diagnosis and treatment for women with breast cancer. The important advances in research and care that you help make possible improve the future for women and families everywhere.
Thank you for joining us in this mission.
PANCREATIC NUTRITIONAL PROGRAM (PNP): A NOVEL WEIGHT REDUCTION PROGRAM IN OVERWEIGHT/OBESE BREAST CANCER SURVIVORS
GOALS: The primary aim of this study is to estimate the change in body weight after dietary intervention. In addition, we are looking at body measurements and blood markers.
STUDY: Postmenopausal breast cancer survivors wear a device that continually monitors their blood glucose levels and are asked to keep a food diary. Weekly for 12 weeks, the food diaries and glucose levels are reviewed. The goal is to learn what foods and mixtures of foods keep the blood glucose between 70 and 100 mg/dL. After 12 weeks, the participants are “on their own,” and at six months, they have a final weigh-in and provide a blood sample for biomarkers.
PRELIMINARY FINDINGS: Recruitment and enrollment are complete. Twenty-one women were enrolled.
The mean body weight at baseline was 170.9 pounds (±20.4 pounds). Two patients dropped out before the completion of the 12 week period, and one developed recurrent disease. Among the 18 eligible women who completed the first 12 weeks, the average weight loss was 10.1 pounds (1.5–19.6 pounds). The average loss of waist circumference was 2.5 inches (gain of 0.4 inches, loss of 5.5 inches).
Among the women whose total cholesterol was above 200 mg/dL, 71 percent reduced their cholesterol below 200 mg/dL by 12 weeks. All women who had triglyceride levels above 150 mg/dL reduced their levels below 150 mg/dL by 12 weeks.
Likewise, among women who were identified as being prediabetic, based on fasting glucose or hemoglobin A1c levels, all were within normal range at 12 weeks. Six-month testing will be completed in August. Among the 15 women eligible for six-month testing, eight (53 percent) have completed the testing. Of those, seven (88 percent) have maintained their positive results.
NEXT GENERATION DRUG DISCOVERY
My lab is conducting research to improve the efficiency of drug discovery by more than 10,000 times with an innovative method to place ~1 billion different molecules on a chip the size of a microscope slide. These chips will be used to identify which molecules are potential drugs to target proteins that other researchers at City of Hope have identified as promising new areas for treating human disease.
There are several significant steps to creating these chips that I laid out in my initial application:
- Develop a method to make ~1 billion small cups on the surface of the chip.
- Synthesize molecules on miniature beads, along with a barcode that identifies the bead.
- Immobilize the beads in the miniature cups, resulting in 1 billion molecules permanently arranged in a grid pattern on a slide.
- Use the tags to decode what compound is at each position, resulting in a reusable glass slide with 1 billion molecules that can be screened over and over to identify potential drugs.
- Pass solutions of protein over the chips and see which molecules bind to the protein.
When I first applied, we had only accomplished steps one and two. In my first update, we had completed all five steps for small collections of molecules. By my second update, we had completed steps one and two again for our first large-scale library, which has 2.6 million molecules in it. While preparing this library, we also completed additional critical steps:
- Developed a new quality-control method to check the integrity of the molecules on each bead.
- Optimized a rapid imaging microscope to allow for fully imaging a chip with 1 billion molecules in several hours.
- Developed a new data processing back end to handle the huge amounts of data we will be collecting.
In this update, I am excited to share that we have now completed all five steps for our 2.6 million-membered library and have completed a key demonstration that the technology truly works. We exposed a chip containing this library to a protein that is known to bind a specific molecule present in the library and were able to observe binding of the protein to this molecule on the chip. This is very exciting, because it demonstrates that we are able to fish out one powerful molecule from a collection of 2.6 million. Moreover, we also identified new molecules that bind this protein, representing the first time our system was used to find new molecules of interest.
FEB 2015 - Proof of principle synthesis of molecules on beads; prototype chips
SEP 2015 - Small libraries (seven molecules max.) immobilized in chips, decoded and screened
JUNE 2016 - Medium (2.6 million molecules) library synthesized, immobilized and decoded
JUNE 2017 - Screened medium library — validated for a positive control and discovered new molecules of interest
JUNE 2018 - Goal: Synthesize, immobilize and decode 100 million-membered library; then 1 billion
Jacob Berlin, Ph.D.
RNA BIOLOGY IN CANCER CELL RESPONSE TO CLASTOGENIC THERAPEUTICS
I am pleased to provide this update on our pilot project to the Circle 1500 members. The goal is to understand how RNA biology affects how the cancer cell responds to clastogenic therapeutics.
A clastogen is an agent that causes DNA damage, which can be lethal to cancer cells. Radiotherapy is a clastogen, as are many chemotherapeutics. However, cancer cells can evade this therapeutic approach by activating DNA damage repair pathways. We seek to define these pathways in order to predict how well an individual patient’s tumor might repair the DNA damage and hence respond to therapy. This knowledge could be used to develop biomarkers for personalized medicine, and it may make it possible to develop drugs that can block DNA repair in cancer cells, thereby improving the ability of clastogens to kill cancer cells.
For over 10 years, my research at City of Hope has been devoted to DNA repair pathways and the cellular response to clastogens. This pilot award has provided an opportunity to expand our efforts to define the role of RNA molecules in this process. Namely, we are performing experiments to understand the links between RNA molecules and the function of the BRCA1 tumor suppressor gene, which is critical for a specific type of DNA repair.
Recently, with the support of Circle 1500, we investigated how blocking a cell’s ability to process RNA molecules causes a defect in the DNA repair of the BRCA1 gene. RNA molecules are made in the cell, with large segments that need to be removed, which is called RNA processing. We have found that cells lacking a key RNA processing factor, or treated with an anticancer agent that blocks RNA processing, show reduced recruitment of BRCA1 to sites of DNA damage, as well as defects in DNA repair.
We are currently performing additional experiments to further test this hypothesis. This work is significant because it raises the possibility that defects in RNA processing could be biomarkers for clastogen sensitivity in tumors, making them a target for personalized therapeutics.
- Jeremy Stark, Ph.D.
OUR RESEARCH: Our research team studies the biological mechanisms involved between modifiable risk factors and the development of cancer in women, with our ultimate goal being the prevention of cancer.
PROGRESS: This year, our team made excellent progress on this eight-month pilot exercise trial consisting of four different community-based exercise programs among women with no history of cancer or diabetes. Exercise regimens included walking (low-intensity cardio only), Zumba (high-intensity cardio only), Curves (low-intensity combined) and CrossFit (high-intensity combined). It is very exciting to report that within only three days of opening the study, we hit our accrual goal of 40 women and enrolled a total of 46 women into the study. Women were randomized to join one of the four exercise programs and were allowed to choose a facility close to work or home.
At the beginning of the study, we collected blood samples to establish baseline measurements: weight, body fat and body size; the ability of each woman’s body to repair her DNA and to respond to inflammation; glucose levels; and RNA sequencing, which tests every gene in the body and determines whether it is on or off. Each woman also filled out an online questionnaire for background, health and quality-of-life data.
In March, most of the women finished their first four months and repeated all of their measurement testing. For the second four months, women were allowed to choose their preferred exercise program. At eight months, we will be able compare all the results and adherence rates based on whether they were randomized or were able to choose.
PRELIMINARY RESULTS: We are currently analyzing the measurement, biological and questionnaire data from the first four months. The preliminary adherence data for the first four months shows that women were most adherent to walking, then to Zumba, then to CrossFit, then to Curves. During the second four months, when women were allowed to choose their exercise group, the majority chose CrossFit or walking, with a few choosing Curves or Zumba. So far, the women are being more adherent to exercise regimens they have chosen vs. when they were randomized, and that data will be compiled and confirmed at the end of the study.
WHAT’S NEXT: In July 2017, the majority of women will be finishing their eight months of exercise and testing, and the study will be completely finished at the end of August. We have collected a tremendous amount of pilot data to develop a larger study and will be writing larger grants this year. The team and I are very eager to report our final results to you in the next few months.
- Jessica Clague DeHart, Ph.D., M.P.H.