Research Grants Awarded
Novel Targets For Treatment And Detection Of Inflammatory Breast Cancer
The Hypothesis for our studies in this Susan G. Komen Promise Grant is that hallmarks of IBC will guide development of both a diagnostic for earlier detection of inflammatory breast cancer [IBC] and for development of specific therapies that are selective for more effective treatment of IBC patients. Inflammatory breast cancer [IBC] is the most lethal form of breast cancer, with little understood about signatures of this disease to ensure its detection and effective treatment. IBC deviates from the genotypic and phenotypic characteristics of ductal or lobular breast tumors, is not detected as a lump in the breast, and is commonly misdiagnosed as an infection, leading to an IBC patient population with metastatic disease [usually at least stage IIIb] upon first diagnosis, with a resultant overall median survival rate that is very low. Imaging modalities of mammography and ultrasound typically used for breast cancer detection are not useful for detection of IBC. This form of breast cancer often presents as a mosquito bite, with an assymetical increase in the size of one breast, redness, warmth, induration, edema, wrinkled skin, termed ?peau d?orange?, with an inverted nipple. These symptoms are due to the presence of cancer cells in the subdermal lymphatics. IBC is diagnosed by biopsy and by imaging modalities including magnetic resonance imaging (MRI) and positron emission tomography (PET). Past projections were that IBC accounts for 2-5% of the patients with a breast cancer diagnosis in the United States with a predominance of African-American and Hispanic women diagnosed with IBC, however there is a disturbing trend noted in the past decade that women of all ethnicities are being diagnosed at a higher incidence with IBC at early ages, i.e., younger than 40 years of age, with highly aggressive, locally advanced disease. Globally, IBC is estimated to account for 20% of all breast cancers diagnosed, with a preponderance of IBC in such countries as Algeria, Morocco and Egypt. This lethal form of breast cancer has a 3 year survival rate of less than 25% which may be based on treatment of IBC patients with conventional regimens of surgery, chemotherapy and radiation developed for other types of breast cancers. Few pre-clinical, translational, or clinical research studies thus far have focused on developing an earlier diagnostic, and treatments specific for IBC patients. It is thus not surprising that there has been no change in mortality rates of IBC patients in over 30 years. Our Komen Promise program is comprised of a multi-disciplinary team which includes IBC patient advocates breast medical breast oncologists, breast surgeons, pre-clinical investigators, nanotechnology experts, investigators with expertise in experimental therapeutics, imaging specialists in PET and MRI, pathologists, radiologists and experts in genomics as well as experienced internal advisors, external advisors who have made significant contributions in the field of IBC. This team is collectively focused on developing methods for identification of specific genomic and proteomic signatures of IBC for its diagnosis, on developing therapeutic approaches specifically for treatment of IBC, and enhancing imaging approaches to assist in detection and evaluation of effectiveness of treatment regimens for IBC patients, with the overall goal of improving the rate of survival of IBC patients. This research team is based primarily at The University of Texas-M.D. Anderson Cancer Center, which is home to the first clinic worldwide, dedicated to IBC treatment and research, The Morgan Welch Inflammatory Breast Cancer Research Program and Clinic. Globally, our IBC clinic has the largest IBC patient population and has an established tissue and serum bank with a base of 100 IBC patients. In addition, this team has developed 2 novel IBC cell lines, with development of pre-clinical animal models of IBC underway with other studies that have identified IBC stem cells from pleural effusion and blood of IBC patients. These resources will be the basis for development of clinically relevant signatures of IBC and therapeutics specifically for treatment of IBC patients. Our Komen Promise program includes an Administrative core to provide fiscal oversigh, oversight of regulatory aspects including internal review board approval, appropriate isolation, tracking, and use of IBC patient samples, maintenance of confidentiality, animal assurances, scheduling research meetings, educational programs and seminars, oversight of trainees to ensure the future of IBC patient care and research, to ensure that progress is communicated to our multi-disciplinary inter-institutional IBC team, to schedule interaction with our IBC patient advocates and research team members on a biweekly basis, and to schedule bi-annual assessment with a team of patient advocates, internal advisors and external advisory board members. To achieve our goals of identifying signatures for an IBC diagnostic, and development of IBC specific therapies, the following Specific Aims are proposed: Specific 1. Define and validate signatures of IBC in serum and pleural effusion from IBC patients, IBC cell lines, and IBC stem cells for development of an IBC-specific diagnostic. Specific Aim 2. Determine the role of inflammatory molecules and signaling pathways in growth, invasion, and microvessel development in IBC xenografts and in IBC patient tissue samples and pleural effusion fluid. Specific Aim 3. Evaluate effectiveness of selective inhibitors in pre-clinical studies followed by a Phase I Clinical Trial in IBC patients.
The hypothesis for our studies in this Susan G. Komen Promise Grant is that hallmarks of Inflammatory Breast Cancer [IBC] will guide development of a diagnostic for earlier detection of IBC and for development of specific therapies for effective treatment of IBC patients. IBC is the most lethal form of breast cancer, with no significant changes for diagnosis, treatment, or overall median survival rate for IBC patients in over 30 years. Although previous projections were that the majority of IBC patients in the United States are African American and Hispanic, there are recent reports that over the past decade there has been a significant increase in the number of women of all ethnicities being diagnosed with IBC. IBC patients present with very aggressive disease at much earlier ages, i.e., less than 40 years of age, with an overall 3 year survival rate of less than 25%. Globally, IBC accounts for 20% of all breast cancers diagnosed. Although IBC occurs less commonly than other types of breast cancer, there are a disproportionate number of deaths due to IBC which is likely based on the lack of effective means to diagnose IBC at early stages and the lack of therapies developed to specifically treat IBC. IBC presents as a completely different disease compared to other forms of locally advanced breast carcinoma. IBC is usually misdiagnosed due to the symptoms with which the patient presents, including tender, swollen, reddened breast, induration, edema, warmth, rippled orange-like skin texture on the breast, defined as ?peau d?orange?, nipple inversion or flattening, and swollen lymph nodes under the armpit and neck. Unfortunately, symptoms of IBC are often mistaken as an infection or mosquito bite, leading to the prescription of antibiotic therapy, which delays correct diagnosis of IBC. IBC is not detectable by mammography or ultrasound but requires more sophisticated imaging techniques such as magnetic resonance imaging (MRI) or positron emission tomography (PET) scanning. The inflammatory response observed in patients with IBC is due to the clogging of the IBC tumor cells within the lymphatic channels under the skin, which can be visualized by a biopsy of skin. Patients with IBC are commonly diagnosed after they have developed locally advanced disease. Women with IBC often develop pleural effusion, in which pleural fluid filled with tumor cells and IBC stem cells accumulates in the pleural cavity and must be drained on a regular basis. Conventional therapies developed for treatment of more commonly diagnosed ductal or lobular breast carcinoma are also used as the standard treatment for patients with IBC, however, these are largely ineffective. Unfortunately, the major advances in detection and treatment of other types of breast cancer have had no impact on the morbidity and mortality of patients with IBC. There are no clinically relevant markers routinely used to diagnose IBC nor are there therapies that have been specifically developed for treatment of IBC, which deviates significantly from the genotypic and phenotypic characteristics of either ductal or lobular breast tumors. In addition, there have been few pre-clinical studies to develop and characterize models of IBC with which to study the etiology and molecular characteristics of IBC. Therefore, the goals of our Komen Promise Grant Program are to identify and then validate clinically relevant signatures of IBC tumors to develop a clinically relevant approach to earlier diagnosis of IBC using serum or biopsy material. In addition, we will also identify targets of inflammation characteristic of IBC for development of selective therapeutics for effective treatment of IBC, using a number of pre-clinical models and novel approaches, ultimately resulting in clinical trials. We have assembled a team of experienced investigators who are working together with IBC patient advocates, internal advisors and external advisors to attain these goals. The research team assembled for our Komen Promise Grant application is composed of IBC patient advocates, breast medical oncologists, breast surgeons, imaging specialists, pathologists, radiation oncologists, and physician scientists and basic scientists who are all focused on significantly enhancing the ability to diagnose IBC at an earlier time than Stage III b and in developing selective therapeutics for effective treatment of IBC, which do not currently exist. To lead our Komen Promise Grant Program team are a clinical scientist and a pre-clinical scientist and involves the first clinic specifically focused on the diagnosis, treatment, and research on IBC, The Morgan Welch Inflammatory Breast Cancer Research Program and Clinic at The University of Texas M.D. Anderson Cancer Center. The time frame for identification and validation of signatures of IBC for diagnostic use in detection of IBC is within 18-24 months, which will then be translated into studies to evaluate the clinical utility of these signatures of IBC within 36 months. We have identified several targets of inflammation and are currently performing studies that will lead to development of treatments specifically for IBC within 36-48 months of initiation of the project, with a Phase I trial in 15-20 patients with IBC planned for months 24-60 of the funding period.