Donations = Metastatic Breast Cancer Research: This is the third in a series of six reports on the research grants METAvivor has thus far awarded.
Grant awarded to Rahul Jandial, MD, PhD for his research on a potential new medication to fight brain metastases.
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2012 Grant Recipient Rahul Jandial, MD, PhD, is a neurosurgeon and researcher at City of Hope Comprehensive Cancer Treatment Center in California. |
Research Project: The goal of this research is to determine the efficacy of a novel drug therapy for HER2+ and Triple Negative (TN) breast cancers that have metastasized to the brain and to establish its potential for use in clinical trials.
Setting the Scene: Metastases comprise the most common cause of malignant disease in the brain, and are diagnosed in up to 200,000 patients per year in the U.S. alone. Primary tumors of the brain (glioma) occur in only 10,000 patients, yet receive nearly the entire focus of research funding and attention for “brain tumors.” Meanwhile, new treatments have evolved that can help slow down the progression of metastatic breast cancer in the bones and in other body tissues. The combined implications of this reality have given rise to a disturbing irony. Because some people are living longer with MBC in these other locations, metastases to the brain, which can take longer to manifest than mets in other tissues, have more time to develop, and are increasingly a first site of relapse in certain types of breast cancer.
Trastuzumab (Herceptin), introduced over 10 years ago, has been found to be an effective treatment for women with HER2+ breast cancer. However, soon after its widespread use, a population was discovered for whom the development and progression of brain metastases became a significant cause of morbidity and mortality. Contrary to past experience, the diagnosis of brain metastases occurs in this group often despite effective systemic disease control. Improving the treatment of brain metastases for women with HER2+ and Triple Negative breast cancers remains drastically under-researched, and any enterprise aimed at responding to this expanding clinical need will be significant.
Background and Objectives: Current treatment options for brain mets are limited to radiation and surgery. Research into chemotherapeutic treatments for brain metastases has been hampered by several obstacles. In the first place, research has largely relied on using long standing breast-brain cell lines that have been cultured in the lab for years, and therefore do not reflect the activity of brain metastases in current patients. Fresh brain mets specimens, obtained during surgery for patients with active disease, would therefore be better for accurate study. Second, because the brain itself blocks access to molecules and drugs via the blood-brain-barrier [BBB], getting new drugs into the brain is a challenge. Third, even if new treatments can be shown to cross this barrier, they may hurt healthy brain cells along with tumor cells.
To overcome these obstacles, Dr. Jandial is obtaining fresh surgical specimens from patients with breast-to-brain cancer who have been treated by City of Hope’s neurosurgical department. These cells are being used to determine the effective concentrations of a novel drug, called GloX1, which can cross the blood-brain-barrier and disrupt a metabolic pathway that is active in the cancer cells but not in the normal brain cells. This disruption can destroy the cancer cells by causing an accumulation of toxic metabolites, while sparing the normal cells.
The development of GloX1 arose from the recognition that many tumors rely predominantly on a metabolic process called glycolysis. Glycolysis is the process by which the body breaks down glucose to produce energy, some of it in the form of ATP, an energy-containing molecule. In normal cells, glycolysis accounts for about 10% of ATP production, but in tumors which depend on glycolysis, the percentage of ATP production can be in excess of 50%. However, a consequence of this enhanced glycolysis in cancer cells is that glucose can decompose directly to yield atomic magnesium, or Mg. The interaction of Mg with proteins, lipids and DNA forms advanced glycation end products which, if not repaired or eliminated, induce programmed cell death, called apoptosis. To protect themselves against this excess Mg, glycolytic tumors that include breast-to-brain metastases [BBMs] overexpress two detoxifying enzymes that are crucial to eliminating Mg. These enzymes, known as GLO1 & GLO2, are involved in the process that converts Mg to D-lactate and prevents the process of tumor cell death from occurring.
It has been found that, without the first one, GLO1, brain tumor cells cannot scavenge for Mg atoms and cannot thereby stop them from forming the end products that induce tumor cell death. Therefore, inhibition of GLO1 is predicted to prevent this detoxification of Mg, significantly increasing the level of these end products and prompting increased tumor cell death. Furthermore, GLO1 can be targeted with the potent and selective inhibitor, bromobenzylglutathione-dicyclopentyl-ester (GloX1), which can permeate the blood-brain-barrier (BBB). Therefore, the study hypothesis is that GloX1 could selectively target breast-to-brain metastatic tumor cells without being toxic to normal brain cells.
The second part of this research will be to determine the efficacy of GloX1 for inhibiting the growth of new breast-to-brain cancer cells. This will be done by transferring the cells into mouse brains and monitoring the presence or absence of D-lactate. Establishing the efficacy of GloX1 could lead to further clinical trials.
Pre-application research: Dr. Jandial’s preliminary research demonstrated that brain metastases do employ the above metabolic adaptations for survival. Because GLO1 converts Mg into lactate, the clinical evidence for GLO1-mediated survival can be found by examining lactate levels in tumors. Elevated lactate levels are often found in tumors, and correlate with poor patient prognosis, decreased disease-free or metastasis-free survival, and shorter overall survival in a variety of cancers. The production of lactate can be non-invasively quantified by identifying its proton metabolite using Magnetic Resonance Spectroscopy (MR SPECT). Prior research demonstrated further proof of active metabolic pathways using Positron Emission Tomography (PET), which showed increased fludeoxyglucose (FDG) uptake in brain metastases relative to normal brain tissue. This body of empirical evidence suggests that GLO1-mediated detoxification is active in brain metastases, and that inhibiting it by inhibiting GLO1 is a valid therapeutic strategy.
Why This Is Important: Amplification of the HER2 oncogene occurs in 25% of primary breast carcinomas and is associated with decreased survival due to breast-to-brain metastasis. In one study, 50% of patients who had breast cancer with systemic, metastatic HER2 disease were either responding to chemotherapy or had stable systemic disease at the time that brain metastasis was diagnosed, and 50% of these patients died as a result of tumor progression. Dr. Jandial’s study is aimed at addressing this, and could lead to the development of a chemotherapeutic agent that can reduce brain mets without harming healthy brain tissue.
In addition, this research could have therapeutic implications for the management of brain metastasis overall, by exploiting the unique metabolic adaptations on which neoplastic cells depend. There is also the potential for the rapid use of these strategies in the clinical setting, because the study is exploring a neuro-oncologic application for a compound that is deliverable to the brain, and could work in a conjunction with brain radiation, the current standard of care. Furthermore, it may benefit investigators of other solid organ tumors which also utilize adaptive mechanisms for toxic metabolite detoxification, thereby contributing widely to the field of oncology.
We look forward to reporting on Dr. Jandial’s progress.
Videos: Dr. Joanne Mortimer, who is one of Dr. Jandial’s colleagues at City of Hope, discussed his research on brain mets in this interview at the 34th Annual San Antonia Breast Cancer Symposium.
Dr. Jandial also serves as a regular contributor to KTLA-TV on a variety of health and science topics. You can see some of his KTLA reports and interviews here.
