Jonathan Hagopian (jhagopia@ucsd.edu)

Graduate Program:  Biomedical Sciences
Lab PI:  Joseph Adam, Ph.D. and Xiang-Dong Fu, Ph.D.
Undergraduate Education:  University of California, Santa Barbara
Med-into-Grad Clinical training area:  Cancer
Main clinical mentors:
Rahul Jandial, M.D. (rjandial@ucsd.edu)
Hoi-Sang U, M.D.  (hoisang@ucsd.edu)
Christopher Kane, M.D. (ckane@ucsd.edu)
Paul Fanta, M.D.  (pfanta@ucsd.edu)

Quotes:  My first rotation with Dr. Rahul Jandial, Chief Resident of Neurosurgery at UCSD, was a shocking introduction to the severity of cancer and brain tumors.  During this experience I was given the opportunity to observe patients in both the clinic and operating room.   Pharmacological remedies are limited for patients with brain tumors because they are commonly unable to cross the blood-brain barrier.  This limitation remains a challenge from a therapeutic perspective”.

“This Med-Into-Grad experience has been fantastic.  Interactions with patients and physicians have intensified my desire to contribute to treatment directed scientific discovery.  With a clinical perspective, the field of cancer biology becomes much more than complex models of molecular interactions, dynamics, and interconnected pathways.  It is about patients with feelings and family.  It is about courage, strength, success, and failure.  It is about life and death.  I plan to stay in the San Diego area following the completion of my thesis.  The contacts I made during this HHMI fellowship will help me to establish a strong interdisciplinary collaboration in which I can develop an interesting and productive post-doctoral experience”

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 research career was spawned by a strong affinity for the ocean.  Unique research experiences funded by the NSF, HHMI, US Fulbright Program, and NIH have paved the way to my current position as a Ph.D. candidate in the Biomedical Sciences Program at the University of California, San Diego on the verge of graduation.  Projects with tropical marine fish, abalone shell proteins, and seaweed chloroplast genomes have satisfied my desire to explore marine systems.  In the years spent working on these projects, multiple personal experiences with close friends and relatives struck by disease, especially cancer, have focused my interests and efforts on topics relevant to biomedical science.  I have done basic research with protein kinases involved in cell-cycle regulation, and my thesis project is investigating protein kinases that regulate constitutive and alternative mRNA splicing by poly-phosphorylation of SR protein splicing factors.  With established links to multiple neurodegenerative states and a growing association with cancer, I am pleased that my thesis research efforts will make a significant contribution to the body of knowledge facilitating the treatment of these diseases.  My interests have evolved from basic science to the development of research that will have a more direct impact on disease states, especially cancer.  This is why I became interested in the HHMI Med-Into-Grad training.   

Medical training and identification of medically-relevant research issues:  This program has expanded my horizons beyond highly focused studies of specific molecular mechanisms in a laboratory setting to a more global awareness of cancer’s effects in the clinical setting, where it directly impacts individuals who face very difficult treatment decisions and severe physical consequences resulting not only from their disease, but those treatment options targeting their malignancy.  My Med-Into-Grad training has involved both classroom and clinical experiences.  I chose cancer as my clinical training area, and the Molecular Pathology of Cancer course organized by Dr. Mark Kamps provided an excellent overview of molecular pathways and mechanisms of cancer biology.  This course was great.  Lectures were given by local professors, from multiple San Diego institutions, who are key opinion leaders in their respective fields.  The Med-Into-Grad seminar series was also excellent, and involved the participation of patients and physicians living with and treating a wide variety of diseases.
            My clinical experience has involved rotations in three distinct areas:  1) Metastatic disease, with UCSD neurosurgeons.  2) Prostate cancer, with the UCSD chief of urology.  3) GI and Hematological cancer, with a UCSD medical oncologist and UCSD director of clinical trials.
            Cancers that metastasize to distant regions of the body are high-grade malignancies that pose a serious threat to the lives and well being of patients.  Of all metastases, perhaps the most ominous are lesions in the brain.  My first rotation with Dr. Rahul Jandial, chief resident of neurosurgery at UCSD, was a shocking introduction to the severity of cancer and brain tumors.  During this experience I was given the opportunity to observe patients in both the clinic and operating room.  Dr. Hoi-Sang U, UCSD Neurosurgery director of research and vice chairman, was often the attending neurosurgeon.   Pharmacological remedies are limited for patients with brain tumors because they are commonly unable to cross the blood-brain barrier.  This limitation remains a challenge from a therapeutic perspective, and surgery provides an advantage by achieving cytoreduction of pathological tissue.  Because of the sensitive nature of the brain, surgeons work carefully to minimize contact with normal brain tissue.  This precaution often prevents surgeons from removing lesions as an encapsulated whole tumor resection.  The tumor is usually cored out through the center and subsequently peeled back away from the brain.  Metastatic cancer is highly evolved and microscopic cells released during surgical resection pose a risk for local recurrence.  The development of therapeutics for direct delivery to the resection area by surgeons could reduce this risk.  Targeted systemic therapies for metastatic cancer are also needed.
            Prostate cancer is the second leading cause of cancer related death among men in the United States.  The standard of care for prostate cancer depends on staging, but generally involves either surgical resection or radiological ablation.  In this rotation I observed many patients in the clinic and operating room with Dr. Christopher Kane, UCSD chair of urology.  Dr. Kane specializes in robotic-assisted laproscopic prostatectomy.  Some of the most interesting conversations I had with Dr. Kane were about the controversial topic of “over-treatment” of prostate cancer.  With the development of PSA screening, many low-volume and low-grade cancers are being discovered in men that could arguably be categorized as clinically insignificant.  Some researchers now estimate that over 300 patients with such a diagnosis would have to be treated to save a single life from prostate cancer.  With this realization, “active-surveillance” is becoming increasingly popular as an option to immediate surgical or radiological intervention.  PSA detection is not a completely reliable indicator of prostate cancer progression, so regular biopsies are critical.  Improvements in diagnostic tools and methods for measuring prostate cancer progression are needed.
            The final rotation of my Med-Into-Grad experience was within the clinical trials division of the UCSD Moores Cancer Center, directed by Dr. Tony Reid.  I was interested to learn more about clinical trials design and implementation.  My research has focused on protein kinases in the lab, so Dr. Reid paired me with a medical oncologist, Dr. Paul Fanta, who is initiating a clinical trial with kinase inhibitors for patients with advanced hepatocellular carcinoma (HCC).  I have seen many patients in the clinic with Dr. Fanta.  In addition to HCC patients, Dr. Fanta treats various gastrointestinal malignancies.  Patients with advanced HCC face a bleak prognosis.  The current standard of care for these patients is the multiple tyrosine kinase inhibitor Sorafenib (Bayer).  This drug, taken orally, expanded median overall survival from 7.9 months to 10.7 months in clinical trials.  Dr. Fanta expects that he can raise the bar for HCC survival by providing patients with Sorafenib in combination with motesanib diphosphate (AMG 706, Amgen).  AMG 706 targets tryrosine kinase receptors that stimulate both angiogenesis (VEGFR1-3) and proliferation (PDGFR and c-kit).  We are currently developing trial protocols, screening prospective patients, and securing funding for the study with Bayer and Amgen.  Although my Med-Into-Grad clinical experience quarter has come to an end, I will continue to work with Dr. Fanta on this trial, and hope to incorporate a research component with samples collected from patients involved in the study.
           
Research collaborations:  In the final phase of my thesis research, I have been developing skills with mass spectrometric analysis of proteins.  Continued improvements in mass spectrometry sampling resolution and bioinformatics are enabling powerful methods of proteomic analysis by both “top-down” and “bottom-up” approaches.  These techniques are capable of high fidelity peptide sequencing and precise mapping of post-translational modifications.  I am interested in utilizing a proteomics based approach for the discovery of novel diagnostics and therapeutics, especially for cancer. 
            The greatest thing about this HHMI Med-Into-Grad experience has been the expansion of my professional network in the San Diego biomedical science community.  Dr. Jandial, Dr. U, Dr. Kane, Dr. Reid, and Dr. Fanta have all expressed an enthusiastic willingness to collaborate in future research projects by providing access to patients blood, lymphatic, and tumor samples, with appropriate consent.  I look forward to working with Dr. Fanta on the HCC clinical trial. 

Long term impact:  This Med-Into-Grad experience has been fantastic.  Interactions with patients and physicians have intensified my desire to contribute to treatment directed scientific discovery.  With a clinical perspective, the field of cancer biology becomes much more than complex models of molecular interactions, dynamics, and interconnected pathways.  It is about patients with feelings and family.  It is about courage, strength, success, and failure.  It is about life and death.  I plan to stay in the San Diego area following the completion of my thesis.  The contacts I made during this HHMI fellowship will help me to establish a strong interdisciplinary collaboration in which I can develop an interesting and productive post-doctoral experience. 

Training in diagnostics & therapeutics, and identification of unmet diagnostic & therapeutic needs: My clinical experience has involved exposure to a full spectrum of malignancies ranging from low-grade prostate cancer to metastatic breast cancer in the brain.  Throughout my clinical training I have learned about diagnostic methods and therapeutics for various types of cancer.  MRI, CT scan, PET scan, and ultrasound imaging modalities are common methods used by physicians to diagnose cancer.  Biopsies and subsequent histological analysis of tumor tissue and surrounding lymph nodes allow precise determination of tumor staging.  Although tumor marker diagnostics exist, no markers are currently available that give positive results only in patients with malignancy and correlate with well with stage and response to treatment.  There is a need for improved methods with novel tumor marker diagnostics for cancer screening of the general population and monitoring of patients in treatment.
            The classic problem with existing cancer therapeutics is lack of specificity.  Standard chemotherapeutic agents are highly toxic because they do not differentiate between healthy and malignant cells.  New reagents that target the active site of protein kinases are also highly toxic because of the conserved nature of this domain and the resulting inhibition of multiple pathways by these drugs.  Therapeutics are needed that specifically target malignant cells.  The discovery of novel tumor cell properties and surface antigens would make this possible.   
           
 
Diagnostic & therapeutic collaborations:  Research to develop novel diagnostics and therapeutics by proteomic analysis will require a strong collaborative effort between physicians, protein biochemists, cell biologists, and bioinformatic specialists.  San Diego is one of the few places in the world that is home to the very best in all of these fields.  Strong collaborative possibilities exist within my UCSD network:

           
Advice for new trainees--autumn preparatory quarter:  Take time to explore available clinical faculty in your field of interest.  Dr. Kaushansky will give good recommendations for potential mentors, but you will also find great contacts through your own individual networking efforts.  All of the physicians I worked with agree that there is a great need for increased interaction and communication between physicians and scientists.  The participation of Ph.D. candidates in this Med-Into-Grad training is developing professionals to bridge the gap.   
                       
Advice for new trainees—winter clinical training quarter:  Get started early.  Making initial contacts with doctors can be challenging.  Attend clinic, board meetings, seminars, and surgeries.  Talk to patients.  They are often very willing to share their experience regarding the diagnosis and treatment of their disease. 

 Advice for students observing surgery in the Thornton and Hillcrest operating rooms:

The first thing to do is make contact with UCSD surgeons in your field of interest.  Set up an appointment by email or telephone, and be sure to mention your affiliation with the HHMI Med-Into-Grad Program, under the direction of Dr. Kamps and Dr. Kaushansky.  In your meeting, express that you are interested in observing patients in both clinical and surgical settings.  If you are invited to observe a surgery, coordinate with the surgeon’s case manager to identify procedures that interest you.  They can tell you exactly where the procedure will take place.  Do not bother the surgeon with logistical questions.  You must wear your identity badge at all times in the hospital, and your first challenge will be to find scrubs to wear in the OR.  Both hospitals have an office adjacent to the OR that provide scrubs to medical students. You will need to leave your drivers license with the nurse until you return the scrubs.  They will direct you to the locker rooms where you can change and leave your clothes.  There are no lockers for medical students, so do not bring valuables.   Do not wear long sleeves under the scrubs, but a T-shirt will help to keep you warm in the cool operating rooms.  Any clean pair of shoes will be acceptable in the OR.  Transfer your identity badge to your scrubs.    A hair cover must be worn at all times in the hallways and rooms of the OR.  Check the “case board” to confirm that your procedure is all set for the time and room you expected.  Outside of every surgical room is a selection of face masks.  You must have a face mask on before entering a surgical room, choose one that is comfortable to you.  Wash your hands before entering the surgical room.  Once inside, find a space that is out of the way of nurses, residents, and attending surgeons.  Stay away from sterilized equipment.  Optical and robotic equipment covered with plastic bags are sterile, and must not be touched.  If you even get close to these things expect some verbal reprimand.  Write your name on the procedure board under medical students, and let the surgeon know that you are present.  Find a good spot to observe the procedure.  If needed, use a metal stand to gain height for a better perspective.  Procedures that utilize optical equipment can be observed on monitors.
 
Take home perspective on Med-into-Grad at UCSD:  Simply stated, this is an opportunity that should not be missed.  The HHMI Med-Into-Grad program was an excellent experience.  If you are interested in biomedical research, this program will reveal the true significance of your scientific efforts.