Jose Morachis (jmorachis@salk.edu)
Graduate Program: Biology
Lab PI: Beverly Emerson, Ph.D.
Undergraduate Education: University of California, Riverside
Med-into-Grad Clinical training area: Hematology/Oncology
Clinical mentor: Lyudmila Bazhenova, MD; email: lbazhenova@ucsd.edu
Quote: “After completing MIG training, I feel much more comfortable with my judgment towards deciding what specific questions to address at the “bench”. I have a stronger understanding of some of the most important needs towards cancer biology and I feel it will have a long-term impact as I progress through my doctoral research and beyond. It also allowed me to make new connections with clinicians whom are welcoming and interested in providing their clinical expertise that may be vitally important for bench research and vice versa”.
Rationale for Med-inito-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 personal experiences of seeing family and friends suffer through the physical and emotional pain of cancer and cancer treatments have fueled an increasing interest in applying my research towards understanding cancer biology. My PhD training has focused around the tumor suppressor p53 and its role in controlling cell fate decisions. Mutations in the p53 gene are found in over 50% of all cancers (70% in lung cancers) and its primary role is as a transcription factor where it regulates the expression of an array of genes. Of these, target genes controlling apoptosis (cell suicide) and cell-cycle arrest are particularly relevant to cancer. My thesis work involves understanding the role of the transcriptional machinery (RNA Pol II, TFIID, etc) and the promoters of several p53 target genes in influencing the framework on which p53 is able to function. I have found that the promoter sequences themselves play an important role in dictating different kinetics of transcriptional activation and re-initiation. My training has provided me with a strong foundation for molecular and biochemical research, however, I would like my research to have the biggest impact possible towards understanding cancer biology. For this reason, I felt I needed a stronger foundation of the current cancer therapeutic and diagnostic needs. The Med-into-Grad program seemed to be the best opportunity available and I am happy to have gone through the training.
Medical training and identification of medically-relevant research issues: During my Med into Grad fellowship, I joined the Oncology Specialty Training Program (STP) and focused on lung cancer. Lung cancer is one of the most common forms of cancer, yet remains one of the least treatable. In 2007, lung cancer accounted for approximately 15% of all cancer diagnoses and 29% of all cancer deaths. I was fortunate to be under the guidance of Dr. Bazhenova, an expert in lung cancer oncology. At the UCSD Moores Cancer Center and Hillcrest Medical Center, I learned the basics of doctor-to-patient interaction as well as potential research needs and was fortunate enough to even observe a surgical procedure. The interaction with patients provides a human side and reality that cannot be fully appreciated in books or journals. The most beneficial aspect of my medical training came from analyzing several cases during tumor board meetings in which the whole team of oncologists, surgeons, radiotherapists, nurses, and pathologists would gather and discuss the diagnosis from the presented evidence and potential treatment options. Several areas of expertise are needed in the lung cancer field since it is one the most common and lethal cancers. Understanding the molecular complexity from which lung cancers arise is still an imperative since many factors are involved. These include; genetic predisposition (many genes involved), environmental factors (smoking, pollution, or man-made chemicals), and age. While therapies have improved, many still fail as the cancer has already metastasized before diagnosis. Therefore, improving lung cancer diagnostics, along with diverse therapeutics, will be a very rewarding step no matter how small the improvement.
Research collaborations: During my Med-into-Grad training I identified a need to further identify diagnostic markers that may allow for better diagnosis and thus improve tailored chemotherapy for lung cancer. Although I do not yet feel ready to take on a direct collaboration at this point of my career, the relationship I have established with Dr. Bazhenova has opened my eyes to this possibility for the future. I also learned the necessary regulations and extra oversight required to initiate and conduct research that involves patients or patient samples, which includes creating a clear protocol and submitting it to an institutional review board (IRB).
Long term impact: After completing the fall courses and winter clinical training, I feel much more comfortable with my judgment towards deciding what specific questions to address at the “bench”. I have a stronger understanding of some of the most important needs towards cancer biology and I feel it will have a long-term impact as I progress through my doctoral research and beyond. It also allowed me to make new connections with clinicians whom are welcoming and interested in providing their clinical expertise that may be vitally important for bench research and vice versa.
Training in diagnostics and therapeutics: identification of unfulfilled diagnostic and therapeutic needs: There are many diagnostic needs in the lung cancer field. One of the most important, that presented itself numerous times during my training, was the ability to accurately stage a patient’s cancer and to be able to differentiate between a primary and metastatic tumor. There are several stages (I-IV) that are designated to lung cancer patients depending on the size of the tumor, the nodes it has infiltrated, and the level of metastasis. Many times a patient may be diagnosed with a primary tumor in the lung that is subsequently surgically removed. However, if this tumor was a secondary tumor (i.e. traveled from another site) or if it metastasized to other sites at undetectable levels, then the patient has a reduced chance at survival. Knowing this information would be valuable in determining which treatment to proceed with (ie. basic vs. aggressive treatment). On the other end, a patient who only has a single, small primary tumor must still receive chemotherapy since it is unknown whether she has undiagnosed tumors elsewhere. Therefore, the patient must endure the harsh side effects that accompany treatment, even though there is no direct evidence of additional tumors.
Diagnosing lung cancer is quite difficult due to the location of the lungs and the difficulty and dangers of taking biopsies of lung tissue. Methods to obtain pathologic samples are quite invasive (thin needle biopsies, tracheal washing etc.), and less invasive procedures, such as sputum samples, are less effective for diagnosis. I believe research into additional non-invasive techniques should be explored further. High tech instrumentation has been very useful in detecting and locating tumor masses. A computed tomography (CT) scan is used in almost all cases to visualize the lung areas and identify potential lung masses that could be cancerous. A CT scan generates a three-dimensional image of the inside of the thoracic region. Although this is a great tool for detecting tumors and potentially screening patients in a non-invasive manner, the side effects of radiation exposure during the scans is of concern. Another important tool currently used in conjunction with a CT scan is positron emission tomography (PET) scans. During this procedure, a radioactive sugar analog is given to the patient and subsequently concentrates in areas of high glucose uptake, such as a fast growing tumor. The PET scan is highly sensitive and research should be continued in this field to reduce costs and to provide more specific molecules that may aid in better targeting and for research purposes.
Apart from determining the stage of a cancer’s development, the oncology team must also identify the specific type of lung cancer (such as non-small cell lung cancer and its many subgroups, or small cell lung cancer) using primarily histological slides. However, since every cancer is diverse, more complex diagnostic tools should be developed to analyze characteristics such as cancer stage, cancer cell type, cancer cell gene expression profiles, tumor suppressor mutations, and integrity of cell membrane receptors. New tests could be more informative and facilitate better treatment plans.
Importantly, the needs for specific treatments are also still unmet since many of the current therapies rely on molecules that damage DNA to activate apoptotic (suicide) programs of the cell. These “old” therapeutics have been useful overall but have many unwanted side effects including sickness and potential secondary cancers caused by the treatment itself. Therefore, basic research aimed at discovering new specific targets for treatment continues to be of great importance.
Diagnostic and therapeutic collaborations: Previous research studies aiming at targeting the transcriptional machinery with chemotherapeutic agents have provided much information and therapeutic potential. All transcription factors and cofactors must eventually relay the transcriptional activation potential through the mRNA transcriptional machinery (mRTM). The mRTM includes; RNA polymerase II, general transcription factors, mediator, amongst others. One might think that targeting the mRTM would be no different than the DNA damaging agents currently used to treat cancer with respect to specificity. However, targeting the mRTM would be less toxic since it would halt mRNA production leading to cell cycle arrest or death but it would not create many DNA damaging events that may indirectly cause genetic instability (and potentially cancer) in normal cells. Furthermore, it is possible to target transcription specifically. Previous studies, including my own, have shown that inhibiting certain factors deemed critical for transcriptional elongation, such as CDK9 activity, are apparently not necessary on all genes as some p53 targets continue to be activated. Agents such as Flavopiridol and SNS-032 (phase I and II of clinical trials) are examples of drugs that inhibit the phosphorylation of Ser2 of the C-terminal domain of RNA polymerase II. I am currently aiming at developing new in-vitro transcription assays that may be useful in finding novel molecules involved in inhibiting specific genes. I hope this approach will expand the repertoire of tools available for oncologists to treat complex tumors. If a successful assay is developed, I would collaborate with institutions that have large drug libraries (including the Salk) to find drug candidates.
Student-specific experiences: My overall experience during my Med-into-Grad training has been eye-opening. Apart from learning about therapeutic and diagnostic needs, the most intriguing aspect that I could not have obtained in the lab or from a textbook, journal article or symposium, was the human side of cancer. Seeing the sadness and pain of patients has left a lasting impression on me. Seeing the joy and relief of patients whose cancer is shrinking or was eliminated gives hope and satisfaction that anything one can do to help battle these terrible diseases is worthwhile.
Advice for new trainees--autumn preparatory quarter: I recommend putting quite a bit of effort into learning histology and pathology related to your field of interest as early as possible. Perhaps the best way would be to sit in on a histology course to learn the basics of histology and have the opportunity to ask questions. A self-study program is very helpful with time flexibility, but may actually take longer in grasping the basics. Once the basics are learned, self-studying the specifics would be easier.
Advice for new trainees—winter clinical training quarter: My advice for the winter quarter is to have continuous communication with your clinical adviser and continually take notes on what potential needs may be of research interest (maybe not for an immediate research project but down the line in your career).
Take home perspective on Med-into-Grad at UCSD: My overall opinion of this program is completely positive. Although it may take some time away from the bench, if you organize it correctly you can continue to work in the lab while learning many new knew things in the clinic. One of my favorite quotes is “the eye cannot see what the mind cannot comprehend”…and this program really allowed me to see things in a different perspective. I strongly recommend this program if you are enthusiastic about learning more about a specific human disease.