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Spotlight: Principal Investigators
Learn more about our Principal Investigators here at Moores Cancer Center, from their Clinical Practice Focus, Translational Oncology Research, history and hopes of Collaboration, as well as their toolbox of models they use in the laboratory. Meet them first-hand by viewing our interviews below.
If you are interested in collaborating with a Moores Cancer Center investigator, please contact Ida Deichaite.
Hatim Husain, MD, Assistant Professor of Medicine, Division of Medical Oncology, Department of Medicine
Hatim Husain, MD, is an Assistant Professor of Medicine in the Division of Medical Oncology, in the Department of Medicine at UC San Diego. Dr. Husain is a specialist in both lung cancer as well as brain tumors. His work focuses on better understanding the molecular underpinnings of cancer to determine why it forms, how to treat cancer stem-like cells, and how best to prevent metastasis to different organs of the body including the brain. He is working to develop novel therapies to target cancer in the brain and to prevent resistance to established therapies.
Milan Makale, PhD, MSEE, Project Scientist, Neuro-Oncology
Milan Makale, PhD, MSEE, is a Research Scientist-Bioengineer in Neuro-Oncology at the Moores Cancer Center. He is a member of the Basic Science and Translational Laboratory lead by Dr. Santosh Kesari.
Olivier Harismendy, PhD, Assistant Professor of Pediatrics, Department of Pediatrics
Olivier Harismendy, PhD, is an Assistant Professor in the division of Genome Information Sciences at the UC San Diego Department of Pediatrics and is a member of the Moores UCSD Cancer Center. He has a decade of experience in functional genomics and has been working in translational genomics for the past six years, developing assays and analysis for targeted sequencing, exploring the role of regulatory variants in common diseases, and improving the detection of somatic mutations in cancer. Most recently, Dr. Harismendy has been implementing an Ultra Deep Targeted Sequencing assay to detect low-prevalence mutations in clinical samples, with the intent of advancing research to ultimately provide a comprehensive personalized molecular profile of solid tumors.
Keywords: onco-genomics, genetic markers, epigenetic markers, targeted sequencing, high throughput sequencing, DNA adducts, cisplatin, alkylators, platinum agents.
[+] More about Olivier Harismendy, PhD
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Olivier Harismendy, PhD is an Assistant Professor in the UCSD Department of Pediatrics, and a member of the Moores Cancer Center. He is the head of the Oncogenomics Laboratory, and in this laboratory his research interests are in genomics of cancer and tumors. In particular, he collaborates with clinicians and oncologists to study all of the mutations that are happening in cancer, understand how they correlate with certain drug response, drug resistance, and try to use these mutations and all the DNA characteristics of the tumor to identify novel biomarkers to develop novel therapies.
Dr. Harismendy’s laboratory is both a wet lab laboratory and a dry lab laboratory. In the wet lab, they try to develop new assays that use high throughput sequencing in order to identify novel types of biomarkers or to look at the DNA in a novel way. For example, they are currently developing an assay that will allow them to identify the exact location of the adducts in the DNA. These adducts are created by the cisplatin or the platinum agents in therapies. By understanding where the adducts are, for example, they will be able to understand both the mechanism by which they are created and the mechanism through which they get repaired, and therefore understand the mechanism that drives the cell sensitivity or resistance to these very heavily used drugs. In the dry lab part, the genomics and all the sequencing is generated with a large amount of data, and they try to use bioinformatics tools, and they have developed some bioinformatics tools to try to make sense of this data. In the past year, for example, the laboratory has developed a tool that is specifically dedicated to identify very rare and low frequency mutations in the complex tumor. The tumor can get very heterogeneous, either because they are contaminated with novel tissue or because there are multiple clones, so the regular sequencing is not deep enough and sensitive enough to understand this heterogeneity.
p>So, the assay and the analysis that developed was dedicated to look deeper in the DNA and identify those low frequency variants. When they are identified, it can actually help draw back into the evolutionary history of the tumor, understand where each clone came from, and how they developed. It can also help understand the future of the tumor, for example if you detect a clone that might be resistant to a particular therapy, doctors can try to avoid giving this therapy to patients and instead pick a different one. So, this is very important to have a comprehensive landscape of all of the mutations of the tumor at a very high sensitivity. <>In the past Dr. Harismendy and his laboratory have collaborated with some industry and technology partners. In particular, in the wet lab, they were interested in partnering with molecular diagnostics companies or instrument companies who were looking for test cases, to demonstrate that their technology has an advantage over current technologies and current assays. They had a very fruitful collaboration with a company named RainDance Technologies that had a fantastic microfluidic device. They collaborated with them in order to use this device to generate comprehensive DNA libraries for targeted sequencing in cancer. It was a win-win relationship where the company was accessing science and biology, and they were accessing cutting edge technology.
pIn the future, Dr. Harismendy can see his lab continue to do that by providing a platform and a gate for these technology companies to access interesting biological questions, interesting samples, and together publish the demonstration of the advantage of their approach assay technology or instrument.
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Stephen Howell, MD, Professor of Medicine, Associate Director for Research Education and Training
Stephen Howell, MD, is a tenured Professor of Medicine with more than 35 years of experience as a principal investigator in basic science, translational research, and both investigator-initiated and industry-initiated clinical research. Over the past decade, Dr. Howell has focused on understanding the cellular pharmacology of platinum drugs, a class of chemotherapy drugs that trigger cell death in cancerous tumors, and the development of additional drug delivery systems for platinum-containing chemotherapeutic agents.
Keywords: ovarian cancer, drug resistance, platinum drugs, targeted chemotherapeutic agends, paclitaxel, RNAi, interfering RNA, CLL, CD44, multivalent ligands.
[+] More about Stephen Howell, MD
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Stephen Howell, MD, is a Medical Oncologist and Professor of Medicine at the Moores UCSD Cancer Center in San Diego. His area of interest is in ovarian cancer and the mechanisms of drug resistance.
His work involves both attending on the oncology service at the Moores Cancer Center, and running a medium sized research laboratory which focuses primarily on understanding the mechanisms of resistance to drugs and developing new drug delivery systems. Dr. Howell has developed a number of new drug delivery systems that have been launched into the clinic and several of those have been approved. On the side of mechanisms of drug resistance, they focus primarily on the platinum drugs, but also do a lot of work on novel targeted chemotherapeutic agents. His laboratory uses a wide variety of tools, including basic molecular and genetic tools. Dr. Howell also does a lot of study in animals using the large vivarium at the Moores Cancer Center.
p>Dr. Howell participates with a variety of companies. He serves as a consultant to both a number of private companies and public companies, and serves on the board of directors for several companies, both public and private as well. As an example of some of the work his laboratory is are doing with industry, they are working with a company that has a peptide that binds to CD44 and that works very well to kill CLL cells. They have launched a clinical trial at Moores Cancer Center, with the use of that peptide in the treatment of chronic lymphatic leukemia. <>They are also working with another company that has a novel delivery technology, which is based on using multivalent ligands to increase the affinity of a drug delivery system for tumors. Dr. Howell is using that technology to deliver both routine chemotherapeutic agents like paclitaxel and novel agents such as RNAi or interfering RNA.
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David Vera, PhD, Professor of Radiology and Surgery, Co-Director, UCSD Molecular Imaging Program
David Vera, PhD, is Professor of Radiology and Surgery, and Co-Director of the UCSD Molecular Imaging Program at the Moores Cancer Center. His principal focus is the design and synthesis of targeted diagnostic agents capable of measuring receptor density and affinity. Dr Vera’s current research uses receptor-binding technology for sentinel node mapping of melanoma, breast, GI, and urologic cancers. The new agent, Tc-99m-DTPA-mannosyl-dextran (also called Lymphoseek or the generic name, tilmanocept), developed in collaboration with UCSD clinicians and surgeons, recently completed in a Phase III multi-center clinical trial for breast cancer and melanoma.
Keywords: sentinel node agent, fluorescent imaging agent, colon cancer, rectal cancer, prostate cancer, gynecologic cancer, radionuclidic generator, positron emission tomograph, kidney mesangial cells, high resolution pet scanner, high resolution computed tomograph, high resolution gamma camera, high resolution ultrasound machine, radiolabeling, animal imaging techniques.
[+] More about David Vera, PhD
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David Vera, PhD is a Professor of Radiology and of Surgery at the Moores Cancer Center. His training is in biological physics but his profession is in radiochemistry.
Dr. Vera runs a small animal imaging facility at the Cancer Center, but his main purpose is to collaborate with physicians and surgeons to translate imaging agents for cancer research, and the diagnosis and staging of cancer. He has done this twice in the past. A number of years ago he developed an imaging agent that targets a receptor in the liver, and it is now a commercial product in Japan, where there is quite a bit more liver disease than in the United States. Recently Dr. Vera has developed, along with Anne Wallace, Professor of Surgery at the Cancer Center, and Carl Hoh, Chief of Nuclear Medicine, an imaging agent to detect sentinel nodes. This imaging agent was FDA approved in March of 2013, and required about 10 years of early phase development. A company picked it up, and it was then entered into phase 2 and phase 3 clinical trials. The Cancer Center was the largest enroller in the project, and the team was delighted to see the FDA approve it.
p>Recently Dr. Vera has been working with a company called Navidea Biopharmaceuticals that sells the agent. The team is converting it to a fluorescent agent which will allow patients to avoid radioactivity, and also makes it compatible with the surgical robots so that the sentinel node procedure can be performed in a variety of other cancers: colon cancer, rectal cancer, prostate cancer and gynecologic cancers. Essentially the fluorescents, which hopefully will enter phase 1 trial, expands the clinical use of the currently FDA approved agent. <>Dr. Vera is also working with a company in Germany that builds a specialized radionuclidic generator that produces an isotope every three hours, which is compatible with the positron emission tomograph that is used for cancer imaging. He is using the isotope to radiolabel the sentinel node agent and that will allow the team to image with more precision. More specifically, they are interested in imaging the kidney because the receptor that this agent binds to is present in the mesangial cells of the kidney, and that is a cell type that has never been imaged before. The new agent is not only expanding in its indications, but it is allowing cancer surgeons and cancer physicians to detect and monitor disease in an entirely new cell type, that up to this point, was only available via a biopsy.
pRun by Dr. Vera, the Cancer Center also supplies a technology where various investigators and companies can perform imaging techniques on animals. In the basement of the Cancer Center, there are three or four million dollars worth of very high resolution imagers that are capable of doing in animals what is usually done in patients. These include a high resolution pet scanner, a high resolution computed tomograph, a high resolution gamma camera, an extremely high resolution ultrasound machine where one can literally see a mouse heart beating, and a very technical high resolution optical imager. Along with those, there is a radiochemistry lab that allows Dr. Vera to place radioactive labels on to various drugs. <>r. Vera and the imaging team have worked with companies, and permitted a couple of biotech companies in the area to screen their drugs for effectiveness. For example, mice are grown with tumors, and at some point when tumor is at a particular size, they will perform a pet scan with something like 2-fluorodeoxyglucose. The tumor accumulates it, and then a particular drug that is a candidate for a phase 1 trial is administered to the animals. Days later we image again, and if the drug has had effect it will knock out the tumors capacity to bind the radioactive sugar. This is an in vivo and physiologic method for measuring effectiveness in a new therapeutic drug. This is a particular paradigm Dr. Vera uses, but the facility also aids drug companies in investigating biodistribution. It is a very specialized facility, and there are only three of them on the West Coast.
pLstly, the facility is part of an NCI sponsored Molecular Imaging Center. This facility is one of five Molecular Imaging Centers in the country that is sponsored by the National Cancer Institute, and that allows Dr. Vera and others to gather. Various investigators, clinicians, scientists and imaging scientists and radiochemists, such as Dr. Vera, gather together to go about the business of taking drugs, radiolabeling them and then seeing if they can provide the clinical scientists with information that can change the management of a patient with cancer. <>fthere is anything that Dr. Vera’s work or the Molecular Imaging Center can aid, please give him a call or an email and he would be happy to discuss your problems.
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Rafael Bejar, MD, PhD, Assistant Professor of Medicine, Division of Hematology-Oncology
Rafael Bejar, MD, PhD, is Assistant Professor of Medicine in the Division of Hematology-Oncology. His lab is focused on understanding the genetic changes that drive the development and progression of hematologic malignancies like acute myeloid leukemia and myelodysplastic syndromes. His goal is to translate discoveries into clinically meaningful improvements in patient care with these disorders.
Keywords: hematologic malignancies, myelodysplastic syndromes, acute myeloid leukemia, AML, genetic mutations, CLIA vertified test, biomarkers, cell lines.
[+] More about Rafael Bejar, MD, PhD
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Rafael Bejar, MD, PhD, is a Physician Scientist at UCSD. He works primarily in the Hematologic Malignancies group, focusing on patients who have various types of blood cancers. The research in his lab focuses on myelodysplastic syndromes, which is a type of bone marrow failure disorder that can progress to acute myeloid leukemia (AML), and is characterized by the presence of acquired genetic mutations.
The translational work that he has done in the past looks at these mutations and tries to identify mutations that might be biomarkers of disease, something that tells more information about the patient than already known. In particular, these biomarkers can be used to predict outcomes for patients, whether they can use them to change what they think the prognosis should be, how to direct therapy, and how patients are likely to respond to specific therapies. Dr. Bejar has had success translating this work into the clinic. One of his initial publications looked at mutations that predict overall survival with patients with myelodysplastic syndromes. His laboratory identified 5 genes that had this independent prognostic significance, and was able to license that information to a local company here in San Diego, Genoptix. They then turned that into a CLIA certified test that could be ordered by any physician in the country. So, in a short period of time, Dr. Bejar and his collaborators took something that they discovered in the lab, by studying patient material, and turned it into something that was actually truly a more broadly available test that clinicians could use to change how they care for their patients.
p>He hopes to continue this type of work in the future, by finding biomarkers of disease that predict either outcomes or response to therapy, and translating those into meaningful, clinically actionable events that any clinician can order, through the help of private companies that license their material or contract with Dr. Bejar to help develop these diagnostic tests. <>As far what types of tools he uses in the lab to look at these elements, Dr. Bejar tries to model the mutations he sees in patients in cell lines, so he has a technique for editing the DNA of cell lines to mimic the mutations in patients. This provides a ready resource to look at for drug responsiveness, to see if these mutations predict response to these drugs. He can look at how they change the actual biology of the cells themselves, how they grow, how they differentiate into mature cells and so on, and more importantly how they function. For example, he has a couple of models that look at how neutrophils function in the presence of these mutations.
pAgain, this may help Dr. Bejar understand a little bit better how mutations relate to disease and what areas might be actionable in terms of developing new drugs or targeting new pathways. These are areas where he is looking for collaborative partners in both industry and academia.
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Michael Choi, MD, Assistant Clinical Professor, Division of Hematology-Oncology
Michael Choi, MD, is Assistant Clinical Professor in the Division of Hematology-Oncology. Dr. Choi is a hematologist and medical oncologist specializing in the treatment of patients with blood cancers and other blood disorders, with an emphasis on chronic lymphocytic leukemia (CLL). He is a part of UC San Diego's CLL research team, collaborating with the laboratories of Drs. Thomas Kipps, Januario Castro, and Dennis Carson to help develop new therapies for patients with blood cancers. His clinical research interests include highly targeted novel therapies that can be used to treat blood cancers in a personalize and molecularly-driven manner.
David Cheresh, PhD, Distinguished Professor, Vice Chair for Research and Development, Department of Pathology, Associate Director for Innovation and Industry Alliances
David Cheresh, PhD, is Associate Director for Innovation and Industry Alliances, Vice Chair of Pathology, co-director of the Solid Tumor Therapeutics Program and a Distinguished Professor. Dr. Cheresh studies the signaling networks that regulate angiogenesis, tumor growth, drug resistance and metastasis. He identified that integrin ανβ3 – a receptor on the surface of tumor-associated blood vessels – as a critical biomarker of angiogenesis. He successfully translated laboratory discoveries into biologically-based drugs that are now in various stages of clinical development. Cheresh’s research is widely published, with seven papers cited more than 1,000 times each. Most recently, Cheresh and colleagues have created a novel scaffold-based chemistry approach to stabilize kinases – growth-signaling enzymes – in their inactive state. These studies have led to the development of a first-in-class Raf inhibitor that interferes with angiogenesis signaling pathways.
Keywords: angiogenesis, tumor growth, drug resistance, metastasis, integrin ανβ3, CD61, RAF inhibitor, breast cancer, lung cancer, pancreas cancer, epithelial cancer, allosteric inhibitors, targeted therapies, receptor tyrosine kinases, mouse orthotopic models, syngeneic spontaneous tumors, patient derived xenografts, angiogenic blood vessels.
[+] More about David Cheresh, PhD
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David Cheresh, PhD is a scientist in the Department of Pathology where he is Vice-Chair. His laboratory is located in the Moores Cancer Center, where he is Associate Director for Industrial Relations. His research focuses on mechanisms of tumor invasion, metastasis, and angiogenesis. His laboratory looks for molecular mechanisms that regulate processes associated with tumor growth, invasion, and metastasis that allow them to develop new therapeutics to attack those pathways.
The most recent work in Dr. Cheresh’s laboratory has made use of understanding what takes place during patient therapy, when tumors become resistant to the drugs that patients are treated with. As it stands, most cancer drugs, while they initially have the benefit of shrinking tumors, also facilitate a drug resistance mechanism of one kind or another. They recently reported that in breast cancer, pancreas cancer, and lung cancer, that patients being treated with a certain class of drugs, so-called receptor tyrosine kinases, or targeted therapies, while patients initially respond to these, they all become ultimately resistant to this class of drugs. They have uncovered a molecular pathway that facilitates that resistance, but also converts these cells into cancer stem cells, which are considered the most dangerous and aggressive cells. By understanding the molecular pathway that drives both the drug resistance and the stemness of the cancer, they were able to identify potential targets that could be druggable. In fact, they identified a number of different targets, one of them they now have a drug available for, that was approved for other indications that has been shown in preclinical models, in mouse orthotopic models of lung cancer, breast cancer, and pancreas cancer, to be very efficacious when used in combination with drugs like erlotinib, in which the tumors were originally resistant to. So, as tumors develop resistance to erlotinib, they then bring in the second drug, which targets the pathway that allowed the resistance to take place.
p>They also have uncovered a biomarker called integrin ανβ3, also known as CD61, which serves as both a driver and a marker of these stem-like, drug resistant cancers. Ultimately, it should be possible to now impact tumors that typically become resistant to standard of care. Dr. Cheresh’s work also is involved with exploring the microenvironment of tumors and in particular, how blood vessels invade tumors. The lab has developed certain therapies that targets the blood vessels that enter tumors in a way that allows them to decrease the nutrients of the tumor. <>His laboratory has done a lot of work with industry in the past. They have worked with large companies, smaller companies, and Dr. Cheresh has actually founded a couple of companies to exploit some of the science that they have been doing over the years, and have developed a number of drugs that have been advanced through clinical trials, some through phase 3 trials, and they hope ultimately it will lead to an NDA. The idea here is that they target once again pathways, using chemical and biological approaches to develop classes of drugs, in particular, allosteric inhibitors of kinases, that are able to very specifically interfere with molecular mechanisms of cancer cells and angiogenic blood vessels.
pThey are very excited about the possibility of using these so-called allosteric inhibitors because they tend to also interfere with tumors that might be resistant to standard drugs, because they are attacking some of the same targets that are known, only in a different way. The idea is that they are going after a target that there may be a drug available for, but because the tumor is resistant to that first drug, the laboratory has developed a second drug to that target that interacts with that target in a very specific and distinct manner. They believe that this class of drugs can represent a very potent and specific inhibitor of a number of different cancers that could be refractory to standard of care. <>he Cheresh lab uses a number of tools in their research in the laboratory: using various cancer models, using mouse models of cancer, both orthotopic, syngeneic spontaneous tumors, using a number of patient derived xenografts, and in particular, their focus is on trying to understand how tumors become stem-like and become very aggressive. Their approach is to attack those stem-like drug resistant tumor cells in models of cancer that they have been working on. The lab has also been very interested in trying to find common denominators between breast cancer, pancreas cancer, lung cancer, and other epithelial cancers that drive a general property of drug resistance that may not be necessarily specific to a given cancer. They think there are probably things going on that take place in the epithelial cell, that may be common in many epithelial cancers. What they would like to try to do is exploit what they have found in a way to develop new therapeutic modalities.
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Santosh Kesari, MD, PhD, Director, Neuro-Oncology Program, Professor of Neurosciences, Department of Neurosciences
Santosh Kesari, MD, PhD, is Professor of Neurosciences at UC San Diego School of Medicine, and Director of Neuro-Oncology at Moores UCSD Cancer Center. His research investigates the biology of gliomas with the aim of developing new therapeutics for patients with brain tumors. He has a long-standing interest in neural development and cancer stem cells and is focusing on their role in the formation of brain tumors and resistance to treatments.
Keywords: Brain cancer, brain tumors, glioblastomas, meningiomas, patient-derived xenograft models, cell lines, OLIG2, blood-brain barrier, tyrosine kinase inhibitors, nanoparticle technology.
[+] More about Santosh Kesari, MD, PhD
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Santosh Kesari, MD, PhD, is a Neuro-Oncologist at UCSD. He is a Professor of Neurosciences in the Department of Neurosciences, as well as Director of Neuro-Oncology at UCSD Moores Cancer Center.
His clinical practice is very broad; he treats patients with metastatic brain cancers, as well as glioblastomas, meningiomas, and so on and so forth. Dr. Kesari and his laboratory have been trying to develop focused clinical trials based on each particular tumor type. As they are understanding these days that a tumor that is called a glioblastoma in each patient is different, based on the genetic heterogeneity, and what they try to do is incorporate that knowledge into developing novel clinical trials. The other aspect of what Dr. Kesari does is translational research. His laboratory collects data from all of his patients, including their tumors, their imaging, and their clinical data, and try to correlate patients' treatments to response to those various drugs. One of the unique things that the laboratory does is collect fresh tissue from patients and grow what is called patient-derived xenografts. These are little models of each patient’s tumors that are grown in the lab, in a dish, as well as in mice. People use different terms such as avatar for these models. These patient derived cell lines and models are much more authentic at replicating the disease as well as when they test drugs, he can get a more accurate assessment of whether the drug works or not. He can see a variety of differences in each patient’s line that reflects the differences in the actual human beings and how they respond to treatments.
p>A lot of his focus is on new drug development for brain cancers using these models. He works with a lot of academic collaborators at UCSD as well as outside, and also works with a variety of companies locally as well as around the country and internationally. Most of these collaborations have been testing drugs that the company has developed in his laboratory’s mouse models, because this is much more authentic, and will tell how effective the drug is in that model. <>One of the larger goals of the lab is really to work with a few companies very closely, utilizing their whole pipeline of drugs, and looking at combinations of drugs in these specific models. Dr. Kesari want to try to correlate one or several drugs to specific subtypes of glioblastomas, and that information would be very valuable in developing smarter prospective clinical trials of testing a combination, based on the genetic subtype of glioblastoma.
pDr. Kesari’s other area of interest is understanding whether the drug gets into the brain. It is amazing how often drugs are developed for brain cancers, but there is no understanding whether the drug gets into the brain. So, in his same mouse models and actually in his patients, he is very interested looking at drug levels in the brain tissue as well as in the spinal fluid in these patients, to get a better understanding of how much drug got in, and if it had activity using biomarkers. <>ne of Dr. Kesari’s big interests in the translational realm is developing new drugs for glioblastomas. It has been very exciting working at UCSD, along with the variety of collaborators here at the San Diego Super Computer Center and the Chemistry Department, etcetera. One of the things the team focused on early on was to develop a drug for OLIG2, which is a transcription factor that is expressed exclusively in glioblastomas. With this group of chemists and the Super Computer scientists, the collaboration team was able to model this protein, and then in silicone, develop compounds that disrupt this protein function. They have early evidence, with a list of compounds that do this, and this has been formed into intellectual property and has been licensed out to a local company, which had been very exciting for Dr. Kesari.
pH has tried to address the issue of blood-brain barrier, getting across the blood-brain barrier, and they have developed nanoparticle technology that also gets a variety of tyrosine kinase inhibitors across the blood-brain barrier more effectively. They have shown proof of concept that this helps improve the effectiveness of these small molecules in glioblastoma, and getting them across the blood-brain barrier. <>thas been really exciting developing a team approach, and utilizing all the resources at UCSD to really pull together new approaches to treat brain tumors.
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Christina Jamieson, PhD, Assistant Professor, Department of Urology, Department of Surgery
Christina Jamieson, PhD, is an Assistant Professor in the Department of Urology and the Department of Durgery. Her laboratory is located in the Moores Cancer Center, where she does research on urologic cancers, with a special focus on prostate cancer that has metastasized to bone, using patient-derived xenograft models and 3D in vitro models. She is applying her expertise in genome-wide analyses of prostate cancer tumors and primary patient-derived tumor models to translate next generation genomics on prostate cancers into practical applications and novel therapies that will improve and, she hopes, eventually transform patient care.
Keywords: Prostate cancer, patient-derived xenograft models, intra-femoral prostate cancer xenograft, sub-cutaneous prostate cancer xenograft, microCT imaging, bone metastasis, orthotopic models, fluorescent and MRI imaging technologies.
[+] More about Christina Jamieson, PhD
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Christina Jamieson, PhD, is an Assistant Professor in the Department of Urology and in the Department of Surgery. Her laboratory is located in the Moores Cancer Center, where she does research on urologic cancers, with a special focus on prostate cancer that has metastasized to bone.
While most cancers that go to the bone produce mostly or almost entirely this bone thinning, or osteolytic bone lesion, prostate cancer causes a mix of this bone overgrowth, or osteoblastic, and the bone thinning, osteolytic lesion. It has been much more of a problem to try and attack this aspect of advanced prostate cancer. Some of the therapies that have been developed try to mitigate some of the effects of the bone lesions, such as bisphosphonates or rec ligand inhibitors such as the denosumab treatments. Those treatments have not been very successful for prostate cancer bone metastases, because there is a unique interaction of the prostate cancer with this bone microenvironment.
Dr. Jamieson has developed models derived from patient bone metastases tissue, which she introduces into mice that have no immune system, so they are immunodeficient and they do not reject human cells. What this allows her to do is to study the growth of these prostate cancer bone metastases in the mouse bone, and to see how closely, first of all, she has mimicked the growth of the human prostate cancer in the bone environment. In her models she has so far, there a lot of the same effects of this mixed bone overgrowth and bone thinning, or osteoblastic and osteolytic lesion.
The prostate cancer seems to be much more resistant to therapy in the bone environment, so therapies that inhibit the growth of prostate cancer in other locations in the body seem to be inactive when the prostate cancer is growing in the bone environment. Dr. Jamieson wants to understand, with her patient-derived models, so-called xenograft models, with xeno meaning foreigner, so they are putting human cells into the mouse bone microenvironment. It is a mouse that does not have an immune system, so it does not reject the human cells.
She wants to look at not only the interaction, to understand why the prostate cancer likes to grow in the bone and how it can have these devastating destructive effects on the bone, but also understanding how therapy affects the prostate cancer growing in the bone. She has seen with her models so far that some of the standard therapies, androgen deprivation therapies, for example, are used in the clinic, and have been used in some of the patients whose cells were used to derive these models. Some of these therapies are specifically inactive, or the cancer is really resistant to these therapies, when the tumor is growing in the bone, even though if it is implanted it in another location, the tumor growth is inhibited by these therapies. When it is put it in the bone, the tumor can grow as if it is not being treated at all.
Dr. Jamieson is looking to use these models to develop novel therapies, and to understand the molecular mechanisms of why they are resistant and what pathways they are using for the resistance, and then what therapies she can use to eradicate these pathways that are protecting the prostate cancer when it is growing in the bone.
She can also do direct analysis of the patient tumor cells themselves, where she has been doing in-vitro culture models where she can grow the cells in culture and treat them with various therapies in culture. That way she looks at, in the presence of these inhibitory compounds, or compounds that she thinks will specifically inhibit the prostate cancer bone metastases, directly on the patient cells, and allowing her to quickly screen a number of different compounds for their effects on the patient-derived tumor cells.
Another method she uses is patient-derived tumor cells plus the stromal cells from the bone marrow environment that can support this growth. These are called co-cultures, where she puts the tumor cells along with the human cells that support their growth in the bone environment. They are human cells that are derived from bone barrow constituents that are known to support the tumor growth. That combination allows us to look at the growth of the tumor cells and to screen novel compounds with all human cells.
She has a number of assays to measure the viability of the cells. She can do flow cytometry profiling of the cell surface markers to look at differentiation of cells from different stages of prostate cancer, look for prostate cancer stem cell markers that have been characterized such as CD44, and lumenol versus neuro-endrocrine markers. Some of the cells that Dr. Jamieson has appear to trans-differentiate in the xenograft mouse models, and so that is something that she is analyzing in the co-cultures.
The other advantage of looking at the cells directly is that she can look at the functional effects of the various therapies that she is trying to develop, that can, hopefully, inhibit the tumor growth, in the bone specifically.
The other thing Dr. Jamieson can analyze directly in the patient-derived cells from the bone metastatic prostate cancer are the molecular changes that occur. This is a collaboration with Drs. Anna Kulidjian and Christopher Kane in Orthopaedic Surgery and Urology. Because they have the full patient information on their treatment history, they also have access to most of the patients’ primary tumors as well as some of the initial lymph node metastases that were also removed at the time of the tumor. They have done whole genome sequencing, whole exome sequencing in a separate analysis, they have patient samples, and they are doing RNAseq analysis. They have also done gene expression profiling by microarray and validation by quantitative or real time PCR to look at expression of the genes.
From the combination of the genome sequencing and the RNA expression profiling, they hope to identify specific genome changes, and possibly consequent or separate gene expression changes that may be more associated with the prostate cancer growing in the bone.
Another very powerful tool that Dr. Jamieson has is CT scanning, but it is called micro-CT scanning, on a mouse, where, at the same time, she can also do a 3D reconstruction from the CT scan of the bones, so she can look directly at the tumor and how it is affecting the bone. For example, what she has seen with the PCSD1 model, because it produces a mixed osteolytic and osteoblastic lesion, she not only can see when the tumor grows in the mouse bone just like it did in the human bone, that there are areas of bone thinning and area of bone thickening, but that it seems to be regionally confined. For example, the majority of the bone thinning, or osteolytic lesions, occurs at the ends, where it is called trabecular or spongy bone; whereas the majority of the bone thickening occurs along the central shaft of the bone, or in the cortical or dense bone. So, she are exploring why this same tumor produces these different effects on the bone, in the different types of bone that form the femur and some of the long bones, where the tumor quite often metastasizes.
The clinical significance of this, to Dr. Jamieson, is truly does one of these environments really support the cells and the therapy-resistant types of cells more than another, and is there one effect that she really wants to make sure the therapies are targeting, because those are going to be the cells that give rise to the resistant or recurrent tumor growth.
She is looking at being able to image the tumor itself. The micro-CT analysis is in collaboration with Dr. Kulidjian and Dr. Koichi Masuda in Orthopaedic Surgery. Lastly, she has a collaboration with Dr. Quyen Nguyen, Dr. Kane, and Dr. Roger Tsien, who have developed unique fluorescence tagging chemicals that they can inject into the mice, and hopefully, eventually into the patient. These chemicals actually will show the tumor, or show the nerves, and so these are compounds that they hope to be able to use during surgery, so that the surgeon can see the tumor, and hopefully they can remove all of the tumor at the time of the surgery, and where they need to make sure that they clear out the tumor so that they are using good bone for the repair. This is so the surgeon can remove as much of the tumor during the repair surgery as possible.
In addition, they are looking at developing new compounds for MRI imaging. They want to develop these fluorescent and MRI imaging technologies so that they can directly look at the tumor, and when it is growing in the bone, so they know whether the therapies are working or not. That is really their goal, to attack the bone metastatic prostate cancer where it is living, in the bone, so that they can really prevent these terrible effects that prostate cancer has on the bone, but also to stop it from growing in an environment that seems to support its therapy resistance, and give rise to disease recurrence and a population of cells that are really the bad actors in this whole scenario. They have many hypotheses about what kinds of cells they are, but ultimately they want to have these models to eradicate the disease entirely.
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Andrew Lowy, MD, FACS, Chief, Division of Surgical Oncology, Professor of Surgery
Andrew Lowy, MD, FACS, is a surgical oncologist with a primary interest in cancers of the pancreas, liver and GI tract. He has a specialty interest in the management of patients with metastatic disease to the liver and peritoneum. Dr. Lowy is recognized worldwide for his expertise in the surgical treatment of pancreatic cancer and for investigating novel cancer treatments which incorporate surgery and chemotherapy to treat patients with advanced cancer that has spread to the abdomen. He has furthered the development of a promising treatment known as the “chemo bath” or heated intraperitoneal chemotherapy (HIPEC), to treat advanced abdominal cancers. Dr. Lowy serves on the editorial board of the Annals of Surgical Oncology, and is the co-chair of the National Cancer Institute’s Pancreatic Cancer Task Force.
Keywords: Pancreatic cancer, foregut malignancies, metastatic disease, peritoneal metastasis, hepatic metastasis, kinase signaling, RON receptor kinase, heated intraperitoneal chemotherapy, HIPEC, patient-derived xenograft program for pancreatic cancer, patient-derived xenograft models, novel cell lines, high-resolution ultrasound model for tumor development, genetic models of pancreatic cancer, genetically engineered mouse models of pancreatic cancer, biomarker development, novel imaging.
[+] More about Andrew Lowy, MD, FACS
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Andrew Lowy, MD, FACS, is a professor of Surgery and Director of Surgical Oncology at UC San Diego Moores Cancer Center. He is a Surgical Oncologist with a practice focused in GI cancer, most specifically focusing on the treatment of foregut malignancies, such as pancreatic cancer, which is his primary interest. Dr. Lowy also has a major clinical program for the treatment of patients with peritoneal metastasis and use of regional therapy, specifically intraperitoneal chemotherapy delivered at the time of surgery.
Dr. Lowy is most interested in translational oncology initiatives that focus on the treatment of patients with pancreatic cancer as well as the treatment of patients with metastatic disease, that is amenable to surgical therapy, such as the treatment of patients with peritoneal metastasis or hepatic metastasis. He also runs a basic research laboratory that focuses on the study of pancreatic cancer both in development of preclinical models of pancreatic cancer as well as the study of kinase signaling possessions, specifically the RON receptor kinase.
Dr. Lowy has been involved in multiple industry collaborations in the past, and has several ongoing collaborations with industry to study novel agents in pancreatic cancer. He serves as the Co-Chair for the National Cancer Institute Pancreatic Cancer Task Force, which is tasked with advising on clinical trial development in pancreatic cancer, involving himself in pancreatic cancer research both at the national and local levels, both in terms of basic and clinical research.
His laboratory is very much energized by collaborations with industry, as their focus is trying to get novel therapies into patients, and to be involved in novel therapy development from the bench all the way into the clinic. The laboratory work with industry has involved using their own preclinical models to study agents that they have, studying agents in the context of biomarker development work and even in the context of investigating novel imaging.
Dr. Lowy’s laboratory has numerous tools that can be brought to bear in these types of studies. He has been involved in the development of the first genetic models of pancreatic cancer, and so he has all of the relevant genetically engineered mouse models up and available in the laboratory. The laboratory has done preclinical studies with these models, and so they are very facile at using those models, which requires a great deal of experience to understand and use proficiently. He uses imaging such as a high-resolution ultrasound model to follow the tumor development in these models and to monitor therapeutic response.
He has also developed a patient-derived xenograft program with pancreatic cancer in particular, but also with other tumor types, and has used these models in collaboration with industry as well. In addition, he has developed novel cell lines and other novel preclinical models using cell lines developed from genetically engineered mouse models, so he can perform subcutaneous or othotopic xenograft type experiments as well, which he has done in collaborations with industry.
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Tony Reid, MD, PhD, Executive Director, Clinical Trials, Professor of Clinical Medicine, Division of Hematology-Oncology
Tony Reid, MD, PhD, is working towards developing new therapeutic approaches for the treatment of cancer, primarily gastrointestinal malignancies including colorectal cancer, pancreatic cancer, esophageal cancer and hepatobillary cancer. He has been at the forefront of using interventional radiology to selectively deliver therapeutics directly to the tumor using the tumor's own vascular supply. Dr. Reid leads the Clinical Research unit at UCSD and has pioneered the use of gene therapy and viral vectors to selectively kill tumor cells and enhance the immune response to the cancer.
Keywords: Gene therapy vectors, viral vectors, oncolytic vectors, oncolytic viruses, expression vectors, angiogenesis inhibitors, angiogenesis pathway, nitric oxide pathway, signal transduction inhibitors, EGFR pathway, PI 3 kinase pathway, mTOR pathway, transgenic models, mouse models, oncolytic vaccinia, hepatocellular carcinoma, endogenous enhancer, E1A normal tissue, Ad5 E1a transcriptional control region, E1a, E1b.
[+] More about Tony Reid, MD, PhD
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Tony Reid, MD, PhD, is a Professor of Hematology and Oncology at the University of California, San Diego. Dr. Reid runs the Clinical Research Program, focusing on early phase clinical trials. His clinic work is focused on patients with gastrointestinal malignancies, although a lot of the early phase trials, particularly the Phase I trials, take patients with many different kinds of diseases.
Dr. Reid has done a lot of work in the past with a variety of different molecules, signal transduction molecules, antibodies, even gene therapy vectors, viral vectors, oncolytic vectors. All of these have been very exciting, and have been interdigitated with his laboratory work, which is also focused on oncolytic viruses, gene therapy, and expression vectors.
In particular, his laboratory has been looking a lot at angiogenesis inhibitors in new molecules that affect the angiogenesis pathway. Dr. Reid is particularly interested in some of the new ones that are affecting the nitric oxide pathway, as well as signal transduction inhibitors of the EGFR pathway and antibodies that block that as well. He is also looking at small molecules that affect the epidermal growth factor receptor pathway, the PI 3 kinase pathway, and mTOR pathway.
In the laboratory, Dr. Reid uses a number of different types of animal models, both transgenic and mouse models that look at various tumors, particularly pancreatic, colon, gastrointestinal stromal tumors, as well as melanoma tumors that have different types of mutations and drug resistance.
Dr. Reid is particularly interested in oncolytic viruses. He has used adenoviruses as well as vaccinia, and he currently has a clinical trial open looking at oncolytic vaccinia viruses, showing significant progress in patients with hepatocellular carcinoma. This has been taken into Phase I and Phase II testing, and now it is into a randomized Phase II trial.
In his own laboratory, he has worked on modifying the adenovirus, particularly modifying the endogenous enhancer found in two different transcription factor binding sites, though really involved in expression of E1A normal tissue, but are dispensable in tumor tissues. By knocking those out, Dr. Reid have been able to make an adenovirus that very selectively replicates in tumor cells. He has gone on to show in mouse models, this has worked very effectively in a broad range of tumor types including melanoma, colon and pancreas. Some of that was work that was published last year in Nature Gene Therapy.
1. Hedjran F, Kumar S, Reid T. Deletion analysis of Ad5 E1a transcriptional control region: impact on tumor-selective expression of E1a and E1b. Cancer Gene Ther. 2011 Aug 5;18(10):717-723. doi: 10.1038/cgt.2011.41.
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Jason K. Sicklick, MD, Assistant Professor of Surgery, Division of Surgical Oncology
Jason K. Sicklick, MD, investigates the novel allosteric kinase inhibitors of drug-resistant melanoma and gastrointestinal stromal tumors (GISTs). He also studies the role of the Hedgehog developmental signaling pathway in cirrhosis and liver cancer development. He is working towards identifying novel therapeutic targets for these conditions and initiating clinical trials to investigate them.
Keywords: Hepatocellular carcinoma lines, Huh7, SK-Hep-1, PLC/PRF/5, HepG2, LX-2, Hepatocyte Line, AML-12, Gastrointestinal Stromal Tumor lines, GIST-T1, GIST882, STS-45, GIST48IM, Melanoma Lines, 1205Lu, SK-MEL-31, SK-MEL-2, SK-MEL-475, SK-MEL-487, MEL1617,MEL1617-R, 451Lu, 451Lu-R, WM-3211, patient derived xenograft models from a selection of primary Gastrointestinal Stromal Tumors, Transgenic mouse models of GIST, FIT and PDGFRA activating mutations, Nod-SCID gamma (NSG) mice for engraftment studies, Transgenic mice expressing GFP-KIT.
[+] More about Jason K. Sicklick, MD
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Jason K. Sicklick, MD, is a surgical oncologist here at UCSD Moores Cancer Center. His clinical practice is a clinical practice based on surgical oncology and the surgical removal of tumors in the abdomen. His clinical focus includes liver tumors, including hepatocellular carcinoma, cholangiocarcinoma, as well as tumors of the pancreas including pancreatic cancer, and pancreatic neuroendocrine tumors. In addition, another focus of his clinical practice involves the treatment of gastrointestinal stromal tumors (GISTs), which are a rare type of sarcoma with approximately 1 case in about 50,000 people in the United States each year. However, these tumors have served as the prototype for developing targeted therapies for patients with solid tumors.
Besides his clinical practice, he also has a translational research laboratory. Dating back to 2005, his lab reported the first paper demonstrating a role for hedgehog signaling in hepatocellular carcinoma. The laboratory also demonstrated at that time that hedgehog signaling plays a role in the viability of the hepatic progenitors as well as hepatic stem cells, which are important in the cirrhosis and fibrosis of the liver. Together, there has now been over 50 papers published in each one of those fields demonstrating that hedgehog remains an important and viable target for treating patients with multiple liver diseases.
His translational research laboratory is now focusing on translating this work into clinical trials, to determine the efficacy of these novel compounds in patients with hepatocellular carcinoma and cirrhosis, as well as developing these for potential other therapeutic targets and cancers. In addition, they have also developed a focus on gastrointestinal stromal tumors. These tumors, also known as GISTs, are tumors that occur due to mutations in tyrosine kinases. Sicklick is now working with industry to develop novel therapeutic agents for targeting these compounds. More specifically, he is looking at using resistance mutations within these tumors or other resistance mechanisms as the focus of laboratory studies. Targeting the sensitive mutations has borne out to be very productive in the treatment of these cancers, but the major problem that occurs is resistance occurs in about 50 percent of people with a median of about 20 months.
This also translated into other tumor types that he has been studying in the laboratory, including drug resistant melanomas. In order to complete these studies he has a large toolbox of assays, both in vitro as well as in vivo that his laboratory is using to do these studies. On the in vitro side they form the standard cell-based assays: viability, apoptosis, flow cytometry, as well as PCR, western blot, immuno blot, and development of cellular assays for targeting these different compounds. Now, on the in vivo side, they have developed some novel methods for studying these interactions including the development of a novel interperenial tumor based model of GIST tumors, where they have taken patient samples from the operating room and directly placed those into mice. This is the first interperenial tumor xenograft model of GIST, which is novel because it allows for the tumor microenvironment and potential for metastatic disease that would not otherwise occur in traditional subcutaneous tumor xenograft models.
The laboratory is also fairly well versed with performing the standard subcutaneous tumor xenograft models. In addition to these two models, they also have transgenic mouse models of gastrointestinal stromal tumors, as well as fluorescently labeled models of KIT development. And more recently, they have developed a model of fluorescent imaging for GIST tumors using fluorescently labeled anti-KIT antibodies, that allows for one to follow the tumors with both via an ex-vivo approach as well as via labroscopic approaches that are performed in the mice themselves.
With regard to the in vitro techniques that they employ, there is a whole host of cell lines available to the laboratory. These include imatinib-sensitive as well as imatinib-resistant GIST cell lines. In addition, vemurafenib-sensitive and vemurafenib-resistant melanoma lines are available as well. These are both in vitro derived as well as those derived from patients that were initially treated on the vemurafenib trial.
The current translational approach to treating cancer is truly a collaboration between industry and academia, and Sicklick believes that in order to progress, we can’t live in isolation, in that there needs to be collaboration between the two groups. On the clinical side, he has experience treating patients with difficult cancers, and recognizing that current medical and scientific approaches to treating these patients has potential for further improvement. Now, with the same token, he recognizes that industry and pharmaceutical companies clearly have also their set of experience and insight into these diseases as well, and Sicklick truly feels that collaboration between surgeons, scientists, clinician scientists, and industry is critical for improving the treatment of patients with cancer and other diseases.
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