Eliot Bourk (ebourk@ucsd.edu)
Graduate Program: Molecular Pathology
Lab PI: Geoff Rosenfeld
Undergraduate Institution: Case Western Reserve University
Med-into-Grad clinical training area: Cancer and Blood Cell Malignancies
Main clinical mentors:
Medical Oncology -- Dr. Joanne Mortimer (jemortimer@ucsd.edu);
Radiation Oncology -- Dr. Catheryn Yashar (cyashar@ucsd.edu);
Radiology -- Dr. Christopher Comstock (ccomstock@ucsd.edu)
Quote: “Through MIG, I learned about the prevalence of estrogen ablation/aromatase inhibitors in the clinic. Therefore, in my thesis, I have decided to place more emphasis on studying the effects of estrogen withdrawal on ER-mediated transcription rather than focusing entirely on the effects of estrogen vs. tamoxifen (EB)”.
Rationale for Med-into-Grad training:
Medical training and identification of medically-relevant research issues:
Training in diagnostics & therapeutics, and identification of unmet diagnostic & therapeutic needs:
Diagnostic, therapeutic, and research collaborations:
Student-specific experiences:
Long term impact.:
Advice for new trainees--autumn preparatory quarter:
Advice for new trainees--winter clinical training quarter:
Take home perspective on Med-into-Grad at UCSD:
Rationale for Med-into-Grad training: My thesis research is focused on the interplay between the transcriptional activity of steroid hormone receptors (especially the estrogen receptor - ER) and inflammatory signaling pathways in development and disease. Most studies of ER have focused on its ability to upregulate the expression of specific target genes, however I have identified a novel class of ER target genes that are directly repressed by estrogen through the corepressor N-CoR (Cell 124, 2006). In collaboration with other members of our laboratory, I showed that some of these genes are reactivated by the cytokine interleukin-1b (IL-1b). This may be relevant in ER-positive breast cancer (up to 80% of primary tumors are ER+), partly because tumor-associated macrophages at primary sites are known to secrete IL-1b, and also because breast tumors metastasize to sites of inflammatory cytokine production such as lymph node and bone.
We hypothesized that this pathway may also affect the ability of tamoxifen, a well known selective estrogen receptor modulator, to repress ER activity in breast tumors. In drafting the manuscript we published, I realized that my knowledge of clinical breast cancer treatment protocol was very minimal and almost entirely derived from the introduction and discussion sections of basic science publications. I applied to the Med-into-Grad program because I wanted to get a better understanding of clinical diagnostic and therapeutic methods for breast cancer so I could identify the important current/future issues on which to focus my research.
Medical training and identification of medically-relevant research issues:
My Med-into-Grad clinical training focused specifically on breast cancer diagnostics and therapeutics at the Moores/UCSD Cancer Center and was divided into three rotations: Breast Imaging, Radiation Oncology, and Medical Oncology. Throughout the quarter I attended the Breast Tumor Board, which serves as the major forum for interaction between the specialists from each of these areas. This structure was very effective in integrating the different aspects of diagnosis/treatment: by the time I was in the later rotations in Radiation Oncology and Medical Oncology, I was beginning to see patients whose mammograms I had seen in the Breast Imaging rotation or in early tumor board meetings.
In the Breast Imaging rotation I learned from the residents and an online teaching module how to spot abnormalities in mammograms, MRIs, and ultrasound images. I also observed diagnostic procedures such as ultrasound-guided core biopsies and the pre-surgery practice of localizing the tumor by ultrasound. Completing this rotation first proved very helpful throughout the rest of quarter in the tumor board because I could clearly follow the imaging reports by the radiologists.
For my rotation in Radiation Oncology I participated in many patient consultations, learned about radiation physics/dosimetry methods, and discussed past and ongoing clinical trials. This rotation was especially interesting because I saw some of the patients multiple times during their treatment and was able to develop a level of trust that allowed them to open up more about their experience with treatment.
During the Medical Oncology rotation I participated in several types of patient consultations, spanning the range of initial diagnosis to mid-treatment to terminal illness, or in some cases notification that the patient’s tumor has gone into remission. One critical piece of knowledge I gained from this rotation was that post-menopausal patients with ER+ tumors are routinely treated with aromatase inhibitors (which block estrogen synthesis) rather than tamoxifen (which is still used for premenopausal patients). This had a direct impact on my research, since I had previously been under the impression that tamoxifen was the standard of care for most patients.
Overall the UCSD Cancer Center appears to be at the cutting edge of technology for breast cancer diagnosis and therapeutics: from the digital mammography and MRI systems for identifying tumors at their early stages, to the experimental use of the Oncotype DX® gene chip for identifying molecular subtypes of tumors (ER+ vs. HER2/Neu+) to enable targeted treatment, to the new clinical trials of cutting-edge brachytherapy and image-guided radiotherapy systems.
Research collaborations:
At this time I have not established any clinical collaborations for my research, but I hope to begin one soon to analyze the expression in breast tumors of an ER corepressor protein that is becoming a significant focus of my thesis research.
Long term impact:
My experience in Med-into-Grad has impacted my perspective as a researcher in a number of ways. In the short term, based on the information I learned about the prevalence of estrogen ablation/aromatase inhibitors in the clinic, I have decided to place more emphasis on studying the effects of estrogen withdrawal on ER-mediated transcription rather than focusing entirely on the effects of estrogen vs. tamoxifen. In the long term, I feel that I am better equipped to establish connections with clinical groups and more comfortable interacting with physicians and patients in a clinical context. This will be a great asset in the future for obtaining information useful for developing research plans and writing grant proposals, as well as for generating the types of collaborations that will lead to meaningful advances in clinical care.
Training in diagnostics & therapeutics, and identification of unmet diagnostic & therapeutic needs:
I am very happy with the training experience I received – I felt that the combination of specialized rotations gave me a comprehensive understanding of the diagnostic and therapeutic tools utilized in breast cancer treatment, and the multi-disciplinary Breast Tumor Board helped me integrate the concepts from each of the rotations.
Screening mammograms and self breast examination are the primary means of initial detection of breast cancer, while further imaging and biopsy and pathological evaluation of the tissue are the staples of diagnostic characterization of the tumor. Beyond the traditional methods for pathological evaluation of biopsies – proliferative index, cellular morphology, immunohistochemistry – a new gene chip called Oncotype DX® is being utilized for certain patients to characterize tumor types based on gene expression patterns. Unfortunately this chip is fairly expensive and not all patients have the insurance or personal resources to afford it.
Treatment of a primary tumor typically begins with surgical resection – lumpectomy procedures are becoming increasingly popular over mastectomy – and often sentinel lymph node mapping or axillary node dissection to determine whether the tumor has spread to lymph nodes. Depending on the type of tumor, resection is followed by some combination of radiation therapy, chemotherapy, and/or hormonal therapy. For patients who have already developed metastatic disease, the only effective options are chemotherapy and, in the case of ER+ disease, hormonal therapy such as aromatase inhibitors.
One particular patient consultation during the Medical Oncology rotation made me acutely aware of an unmet need in diagnostic/therapeutics. This patient was suffering from an advanced case of inflammatory breast carcinoma that left her with a massive necrotizing wound. Her tumor had not responded to any of the chemotherapy regimens the physicians had tried, and as she held her childrens’ hands on the examining table it was obvious she knew that she was out of options and did not have much time left. Compared to the momentous advances in treatment of other breast tumor types over the past 50 years, especially hormonal therapy for ER+ tumors and Herceptin® for HER2/Neu+ tumors, this was clearly an area that needs intense research focus in the future. Sadly it tends to affect women at a much younger age than the other types of breast cancer. One of the problems for this field is that very little is known about the molecular basis of the disease, making it hard to develop targeted therapies. Also, the reported incidence of inflammatory breast carcinoma is fairly low, making it somewhat difficult to acquire tumor samples for molecular analysis.
Diagnostic & therapeutic collaborations:
One of the estrogen-regulated genes I have studied in my thesis research, bone morphogenetic protein-7 (BMP-7), has recently been shown to be overexpressed in a large percentage of breast tumors. I have developed a hypothesis that BMP-7 may be involved in the formation of hydroxyapatite-containing microcalcifications (a major radiological indicator of abnormality) through signaling to tumor-associated macrophages and induction of bone markers like osteopontin/osteonectin, leading to calcification. At this point I have only had preliminary discussions with my Radiation Oncology mentor, Dr. Yashar, who was intrigued by the idea, but I hope to test this hypothesis in the future. If BMP-7 is in fact upstream of microcalcification formation, it could potentially serve as a blood marker for early-stage breast disease.
Student-specific experiences:
One aspect of the Med-into-Grad experience that really stuck with me was witnessing the fear and uncertainty felt by many patients, and the incredible stress they endure over the course of their treatment (many months for some). At the same time, it was uplifting to see the way these patients rose to meet the challenges of coping with breast cancer, and the incredible strength of will that they exhibited. Many of these women work full time, raise their families, go through months of treatment, and still manage to keep in high spirits. I was also impressed by the support of patients’ families and friends: many women arrived at consultations with their husbands, children, or in one case a group of three friends. This seemed to make a significant difference in the level of stress they felt, as the most upset patients I met with were the ones who were at the clinic alone.
Advice for new trainees--autumn preparatory quarter:
Spend some time checking out the website(s) for the clinical group(s) you will be training with, get an idea of the structure of the group and familiarize yourself with faces if possible. Take advantage of the recommended/required coursework for your specialization – for me the medical school’s Hematology course was vital for following the content of the Hematology/Oncology clinical case conferences I attended throughout both quarters.
Also, do your best to communicate your hopes and expectations to your clinical mentor as early as possible. Med-into-Grad is a relatively new program and it is important for your mentor to understand what you want to get out of the experience in order to help you structure the most effective training program
Advice for new trainees—winter clinical training quarter:
I would highly recommend getting to know the fellows and residents in the clinical group early in the quarter. In my experience they were willing and eager to answer my questions (medically relevant or not) and to share and discuss ideas. They are also in an excellent position to introduce you to faculty members who can provide more information on a topic, or potentially serve as future collaborators.
Get to group meetings a little early and introduce yourself to any unfamiliar faces. If the other group members know who you are and why you are attending these meetings, they will be better equipped to include you in the process. If they assume you are a resident or fellow, they may gloss over important background information that they would otherwise be happy to explain in more detail. Also, if they know your background they may be more likely to ask your opinion on molecular/scientific issues and provide an opportunity for you to contribute to the group.
Don’t be afraid to talk to patients when the opportunity arises – the patients I met were very open about their experience in the clinic, as well as excited that scientists are taking such an interest in solving the important medical issues of disease. Of course it would be a good idea to discuss this issue with your mentor first and cover some ground rules about what type of discussions are appropriate – explaining a new topic or finding in your field of research may be very interesting to the patient, but it is important that they not interpret your discussion as medical advice.
Take home perspective on Med-into-Grad at UCSD:
Med-into-Grad is not necessarily suited to every graduate student in the biological sciences: those who are solely focused on normal biology and disinterested in translational applications, those who are too uncomfortable with the difficult emotional situations that sometimes arise in the clinic, or those who are in a rush to finish their thesis research as soon as possible at the expense of exploring additional learning opportunities may prefer to spend their time in other pursuits.
For anyone else who is interested in confronting the difficult task of seeking out the most important research problems and applying the technological advances in biomedical research to improving the state of human health, Med-into-Grad is an excellent mechanism to introduce graduate students to what can sometimes be a rather closed environment to outsiders.
I would recommend the program to anyone interested in furthering their understanding of clinical diagnostic and therapeutic methods, those who had at some time potentially considered attending medical school, and especially those who plan to perform translational research at some point in their future.