Theresa Reno (trini818@gmail.com)

Graduate Program:  Biomedical Sciences
Lab PI:  Richard Klemke, PhD
Undergraduate Institution:  University of California, Santa Barbara
Med-into-Grad Clinical training area:  Cancer
Main clinical mentor:
Dr. Gregory Heestand   gheestand@ucsd.edu
Dr. Stephen Howell  showell@ucsd.edu

Quote:   “My Med-into-Grad training has fortified in my mind the role of translational research in medical science. I now see how completely necessary it is to understand the disease as it presents in the clinic to fully understand the disease in culture. Often, basic scientists fail to see the big picture, as they are completely infatuated with a tiny aspect of the disease, such as a protein in a signaling pathway. We need to adjust our research to what the patients are feeling and the clinicians are observing. In the future, I would like to be a translational scientist and clinician. I will take what I learned in Med-into-Grad and apply it to my future in the clinic and lab."

Rational for Med-into-Grad training:
I am currently studying the function of the novel protein tyrosine kinase Psuedopodium-Enriched Atypical Kinase 1 (PEAK1). PEAK1 operates within the Src/CAS/Crk/Paxillin and Ras/Raf/ERK signaling pathways to promote cell spreading, migration, and cancer progression. Recently, our work has led us to investigate the role of PEAK1 in mediating KRAS/HER2 oncogenesis. We showed that PEAK1 is a novel therapeutic target that mediates KRAS/HER2 oncogenesis and therapy resistance in human cancers. KRAS activating mutations and HER2 overexpression contribute to a poor clinical prognosis, increased aggressiveness, and therapy resistance in pancreatic ductal adenocarcinoma (PDAC). Thus, there is a substantial need to identify targetable biomarkers that promote cancer progression and therapy resistance downstream of KRAS and HER2. We have found that PEAK1 expression is upregulated in parallel with HER2 by oncogenic KRAS and is necessary for pancreatic cancer growth and metastasis in vivo. Biochemically, PEAK1 binds and activates ErbB2 in a Src-dependent fashion to induce ErbB2/Src/BCAR1(p130Cas) coupling. Notably, shRNA or trastuzumab suppression of HER2 increases PEAK1 expression to promote pancreatic cancer growth in vivo and therapy resistance in vitro. My project uses a structure/function approach to further study the mechanism and function of PEAK1 signaling in cancer cell proliferation, migration, and metastasis.

The prospect of training in the Med-into-Grad program revitalized my thinking about basic science research and the understanding of human disease from the patient’s perspective. I will admit that my previous work at UCSD Moores Cancer Center was not easy. Everyday, I was confronted with the reality of the disease in which I study. I have experienced first hand the suffering of a loved one with terminal cancer and I feel that this opportunity was a chance to finally be able to do something, to not sit powerless and unable to help. I felt that my time in the lab was not enough and that doing Med-into-Grad has given me the clinical exposure that I need to confront cancer more efficiently. I also was interested in Med-into-Grad because I believed that it would give me the exposure and didactic knowledge to be able to complete work in the laboratory that will aid in creating a better quality of life for people with cancer. We need translational science to bridge the gap between what we see in the test tube to what we see in the patient. My current research is following the translational route and I saw Med-into-Grad as a way to set up fruitful collaborations that would lead to the expansion of my professional network and facilitate my translational research.

Medical training and identification of medically-relevant research issues: 
I was involved in inpatient and outpatient services and tumor boards in the oncology and blood malignancies track. The inpatient and outpatient services were where we directly interacted with the oncology/hematology staff and shadowed the fellows and attending. I was able to see a myriad of cancer/hematology patients during my inpatient rounds. For the outpatient service, I specifically sought out the specialty that is associated with my thesis research, GI cancers. During the tumor boards, physicians discuss their current patients and seek advice from other physicians about treatment plans and surgical options. Like the inpatient rounds, it was beneficial to go to a few of these tumor boards to get feel for the many different types of cancers and their treatment options. I specifically went to the breast, lung, and GI cancer tumor boards.

The clinical training opened my eyes to the reality of cancer as a disease and not just cells in two-dimensional culture. The grave reality is that only a very small percentage of cancers are really ever “cured”. The clinicians do their best to develop reasonable treatment plans that consider the patient’s survival and quality of life, but too often I witnessed the despairing nature of this disease, diminished quality of life, short life expectancy, and death. The best chance a patient has to beat cancer is for it to be diagnosed early before it has a chance to metastasize and colonize secondary regions. At the patient rounds and the tumor boards, I was constantly hearing the physicians indicating their worry of a possible relapse for patients with moderate to advanced cancer. Also, the chemotherapy and radiation protocols that the physicians have at their disposal are often undependable and insufficient. This is especially true for pancreatic cancer, which has one gold standard chemotherapeutic reagent, gemcitabine, and the other chemotherapeutics are really meant as treatments for other cancers, such as colon cancer. This being said, we, as basic scientists, need to help improve upon early diagnosis by finding relevant biomarkers and changing how we look at treating cancer. We need to take a patient-specific approach. I learned that in pancreatic cancer there are considered to be three different cell types and these cells all respond differently to cancer treatments. Some are resistant to gemcitabine, so it would not be beneficial for a patient to receive this drug. It would be beneficial to conduct more research to understand these issues. Also, basic scientists need to find more appropriate targets for therapeutic intervention.

Potential Research collaborations:
I would like to pursue a collaborative experiment for my thesis research, as that would make it more relevant to human disease. Due to the need for better diagnostics and therapeutic targets, our lab would like to further characterize PEAK1 as a diagnostic marker, critical signaling hub, and therapeutic target in KRAS- and HER2-mediated cancers. This will require a significant amount of patient samples, including tissue and serum samples from cancer patients. Over the past year, we have started to collaborate with surgical oncologists as UCSD Moores Cancer Center, including Drs. Michael Bouvet and Andrew Lowy. I would like to continue these fruitful collaborations and start more with other clinicians that I interacted with during Med-into-Grad.

Training in diagnostics & therapeutics, and identification of unmet diagnostic & therapeutic needs:
I believe that I have a solid understanding of current diagnostics and therapeutics in oncology. Most cancers are diagnosed and staged using a variety of imaging techniques, including PET-CT and MRI, and pathologist examined surgical samples and biopsies. The pathologists use a variety of stains for cancer specific markers that help determine type of cancer, including its origin if considered a metastasis, and the presence of specific genes, such as ER and HER2 in breast cancer and EGFR mutations in lung cancer, that can used to design therapeutic treatments. Neoadjuvant treatment was sometimes prescribed in an attempt to shrink the tumor before surgery if surgical resection was not initially possible.

Currently, a major issue in cancer diagnostics is the timing of the diagnosis and the insensitivity (CEA marker) of current protocols. Many patients present in the clinic with a locally and systemically advanced cancer. Therefore, we need to identify more biomarkers that could be used to identify the presence of a tumor before it has progressed. Also, many cancers become unresponsive to therapies, so it is necessary to develop therapies to target multiple proliferation and migration pathways. What gets in our way of progressing rapidly in these fields is the diversity amongst different cancers; the positive targeting of one protein in breast cancer may have negative effects when targeted in pancreatic cancer. Cancer cells also mutate quite rapidly, so what may work during cycle one might not have any positive effect during cycle two. Finally, many cancer targets are necessary in normal developmental pathways. Disrupting these proteins could lead to deleterious side effects, as is often seen during treatment with many chemotherapies.

Diagnostic & Therapeutic collaborations:
I am currently working on a potential biomarker for pancreatic cancer. The development of PEAK1 as a biomarker and therapeutic target in pancreatic cancer would be extraordinary due to the limited resources for clinicians battling this disease. We need to continue to characterize PEAK1 and test if PEAK1 is detectable in serum. It will also be beneficial to research the role of PEAK1 in other cancers, such as lung malignancies, due to its connections with the ErbB family of growth factor receptors. Utilizing patient samples from clinicians at UCSD is a vital aspect of developing PEAK1 as a target and biomarker. Presently, we are collaborating with surgical oncologists at UCSD Moores Cancer Center, but I would like to expand our collaborations with clinicians from multiple areas, including breast, lung, and gastrointestinal cancers, that I have encountered during my training.

Long term impact: 
My Med-into-Grad training has fortified in my mind the role of translational research in medical science. I now see how completely necessary it is to understand the disease as it presents in the clinic to fully understand the disease in culture. Often, basic scientists fail to see the big picture, as they are completely infatuated with a tiny aspect of the disease, such as a protein in a signaling pathway. We need to adjust our research to what the patients are feeling and the clinicians are observing. In the future, I would like to be a translational scientist and clinician. I will take what I learned in Med-into-Grad and apply it to my future in the clinic and lab.

Student-specific experiences:
All I would like to say is to use every second of the Med-into-Grad experience. It is a wonderful opportunity that should be used to its fullest. Med-into-Grad solidified my wanting to go to medical school after I graduate. I know now that I can have a major impact in the clinic with my knowledge of this disease and being in the clinic can have a positive impact on my research in the lab.

Advice for new trainees--Autumn preparatory quarter:
The Fellows Curriculum Lecture Series is a good resource to get your feet wet with terminology and some basic understanding of different types of cancers. As the quarter goes on, the second hour might be more beneficial for the clinical training. Being in the clinic with very little background in human anatomy can be frustrating sometimes. If the trainee has chosen one or two different type of malignancies to focus on, I would advice them to learn a little of the anatomy of the designated areas and nearby regions.

Advice for new trainees—Winter clinical training quarter:
The physicians that I trained with are very helpful and willing to teach. For inpatient rounds, we contacted the fellow assigned for rounds during that month and asked them when and where to meet at Thornton hospital. Always try to be on time when following the physicians. I found that some of the most significant learning happened before actually making the rounds when the fellow and attending discuss in detail the patients that you are about to see. Again, with outpatient rounds be prompt and courteous. Since it is usually just you and the clinician, you have more contact with the patient and all the documentation is done after the visit, so there can be some down time, but the physician I worked with used this time to bring up teaching points.

Take home perspective on Med-into-Grad at UCSD: 
Med-into-Grad is a great experience that no one should pass up. I would recommend this program to anyone who is working on a project that is or can be made clinically relevant or even to someone who is just curious about the other side medical science. Med-into-Grad has helped shape and motivate my research and it is beneficial to see that what you do in the lab can be translated to the clinic and actually impact peoples lives.