Khalid Shah, M.S., Ph.D.
My scientific research career has been focused on the advancement of novel promising therapies for primary tumors in the brain as well as highly metastatic forms of breast tumors that find their way to the brain. In total, about 30,000 new patients are diagnosed each year with malignant tumor lesions in the brain and most of these lesions remain untreated owing to the complexity of the brain and thereby effecting the quality of life of patients suffering with this condition is often seen deteriorating with time. My personal motivation for studying primary and metastatic brain tumors dates back to the years’ of my postdoctoral fellowship at the Neurology Department of Massachusetts General Hospital and Harvard Medical School. The poor prognosis of individuals at various stages of treatment for primary or metastatic brain tumors that was presented by the clinical fellows was disheartening and that led to my quest for developing novel therapeutics to benefit brain tumor patients.
The current project focuses on developing a promising “stem-cell loaded virus” approach to treat the metastatic breast tumors that have now progressed to the brain. The inherent complexity of the brain is one of the key impediments to development of new and effective therapies. This has been the key contributor to the lack of sufficient therapeutic interventions to manage the condition and the chief cause for the high morbidity and mortality rates. Our group has constantly been striving to overcome this hurdle and develop a therapeutic strategy that could have a significant impact to help save lives of thousands of individuals who are now succumbing to this condition. The “stem cell – loaded herpes virus" approach has been successfully tested in primary brain tumors, which has led to promising results and significant improvements in survival. We are now geared up to extend this promising therapeutic strategy that surpasses most of the conventional barriers to treatments of brain tumors in to metastatic “breast-to-brain” tumors. We strongly believe that this project will have a direct impact on women suffering with this condition and will help restore the normal quality of life of these individuals.
In the United States, breast cancer is the most common cancer in women after skin cancers. Recent data indicates that about 1 in 8 women in the US are likely to develop invasive breast cancer (breast cancer that has spread beyond the layer of tissue in which it developed and is growing into surrounding, healthy tissues). Of these invasive breast cancers, about 35% form tumors in the brain and are referred to as “metastatic brain tumors”. These metastatic tumors in the brain often present with neurological symptoms and are diagnosed by MRI or PET brain scans. Most patients have multiple deposits of tumors at the time of diagnosis and owing to the complexity of the brain, surgery becomes an inadequate therapeutic option. Numerous parallel therapeutic approaches such as stereotactic radiosurgery (SRS), whole brain radiotherapy and chemotherapy have been tested with no promising evidence of improvement of the patient’s quality of life or the overall survival. One major reason for the failure of numerous drugs to treat the tumors in the brain is the blood-brain-barrier that protects entry of certain substances into the brain. Therefore, there is a considerable need for the development of novel tumor-specific therapies that can overcome the challenges that impede effectiveness of current therapeutic options for breast tumors in the brain.
Who are we?
My laboratory at Massachusetts General Hospital and Harvard Medical School in Boston has been focused on developing successful clinically translatable stem cell–based therapies for tumors of the brain. Over the past decade, we have tested and developed numerous tumor specific molecules and we are preparing to embark onto a clinical study using these therapeutic molecules. Based on the fact that oncolytic viruses (viruses that specifically kill cancer cells) and more specifically, the oncolytic Herpes Simplex Virus (oHSV) has emerged as a promising candidate for high-grade brain tumor therapy, we have created a potent variant of oHSV and demonstrated its effectiveness in animal models of brain tumors. Furthermore, to make this therapy more effective, in a very recent study we have proven that stem cells loaded with the oHSV (MSC-oHSV) is clinically translatable and highly effective in a mouse brain tumor model that mimics the clinical setting of brain tumor growth and resection. This study has opened up avenues for testing stem cell based oHSV therapies where conventional therapies have had little impact on the patients like the invasive breast cancers that metastasize to the brain.
What are we proposing to do?
This project is aimed at improving the quality of life and overall survival in women living with advanced breast cancers that have spread to the brain. Specifically, we will test the efficacy of stem cell loaded oHSV in a mouse model of breast-to-brain metastasis that we have recently developed. This mouse model is unique in a way that it allows us to track the fate of the cancer cells and also, our therapeutic cells carrying the virus by non-invasive imaging methods that permit a near real-time tracking of the process going on in the animal. To better understand the process, we have divided the study into two parts –
Initially, we will determine the fate of the systemically delivered stem cell loaded oHSV in the mice bearing tumors. This will allow us to ascertain that our therapeutic cells carrying the virus are actually tracking down all the tumor deposits in the brain.
Next, we will test the therapeutic effectiveness of this stem cell delivered oHSV approach in mouse tumor model of breast-to-brain metastasis and determine how this therapeutic intervention affects that survival of tumor bearing mice.
What do we expect at the end of this project?
At the end of this study, we will have determined the effectiveness of the stem cell delivered oHSV approach in treating metastatic breast cancers that end up in the brain. The outcomes of this study will lead to the development of a novel therapeutic modality in which, at the time of detection of breast-to-brain metastatic lesions, therapeutic stem cells loaded with oHSV can be systemically injected to target these metastatic tumor cells in the brain. This will have a major impact in saving the lives of many patients that succumb to this deadly type of cancer.
Why is this important?
The incidence of brain metastasis has been estimated to be around 35% of metastatic breast cancer patients, which is often associated with neurological symptoms and diagnosed with brain scans using MRI and PET imaging. Most patients have multiple metastatic lesions at the time of diagnosis, making surgery an inadequate therapeutic option on its own. This project will develop rationale based therapies for patients living with metastatic breast cancer.
Who will benefit?
This project is aimed at improving the quality of life in women living with advanced breast cancers.