By Riya Muckom
Rahul Aggarwal, MD, assistant clinical professor at UCSF, specializes in developmental therapeutics and genitourinary malignancies. During his presentation on Early Stage Clinical Trials, he began outlining the scope of the research involved in the pre-clinical studies of a therapeutic/device intended for human use. Aspects of a potential small molecule therapeutic that need to be understood before starting clinical trials are: physical & chemical properties, pharmacodynamics & efficacy (with in vitro proliferation assays and in vivo xenograft models), pharmacokinetics & metabolism (absorption and distribution of molecule), and toxicology (typically performed on animal models). An interesting development in the field is the shift toward quantifying an “Optimal Biological Dose,” rather than a “Maximum Toxicity Dose” the former being a more relevant measurement in biological systems. Inspired by the increases in computational power, a potential area of research in this field involves developing an algorithm to predict the preclinical results of a potential therapeutic based on prior knowledge of molecular structure and similarly tested molecules. Aggarwal shared his work on molecular imaging biomarkers with the vision that they can one day be used in humans as a screening technique to determine the virulence of a tumor and whether or not treatment is required. These biomarkers are an example of a non-therapeutic technology that must undergo clinical trials to be translated from bench-side to bedside.
by Stephen Wilson
Paul Yock from Stanford medical school/Biodesign gave a talk recently on the future of medical technology. Back in the day, he developed a method for performing angioplasty with just one person (it used to require two). Interestingly, when angioplasties were first being performed, there was generally a 40% chance for renarrowing of the artery, and nobody knew why. He then developed a catheter with an ultrasound beacon. This allowed for more highly resolved studies of the coronary artery, and from these studies doctors found that the high renarrowing rate was due to unintentional outer wall damage to the artery from the balloon. This ultimately led to the development of the stint, which greatly mitigated artery damage.
The rest of the talk was a vision for where the medtech field is going in the future. A large percentage of growing healthcare costs are due to the development and application of new technologies. However, not all of them are practical. As the world population grows so does the demand for affordable medical solutions (U.S. Medtech growth = ~1-2% per year vs. India/China = ~10-20% per year).
At Stanford Biodesign, they developed a rigorous workflow for assessing medical needs, conceptualizing solutions, evaluating practicalities, and executing an optimal solution. It comes across as a really well-designed program. However, they largely focus on innovation based around currently existing technology (i.e. improving design, lowering cost, etc.). They don’t really focus on the discovery/innovation of novel technologies to treat unmet need.
by Ioannis Mountziaris
This summerizes a talk by Dr. James Rubenstein, MD, PhD
Brain cancer serves up a challenge for treatment: radiation therapy is extremely damaging to the brain, and chemotherapeutics have difficulty crossing the blood-brain barrier. While modern drugs can specifically target of cancer cells, their delivery to the immune privileged compartment of the central nervous system has been a challenge. Dr. James Rubenstein of UCSF is interested in an alternative approach: utilizing the brain’s unique vasculature to directly deliver drugs to target central nervous system lymphomas. Dr. Rubenstein’s research focuses on drug delivery via the cerebrospinal fluid (CSF), the liquid that bathes the brain, protects it from mechanical shock, and ensures chemical stability.
Using a catheter connected to a lateral ventricle of the brain, Dr. Rubenstein is able to deliver Rituximab, a clinically approved anti-CD20 monoclonal antibody used to treat lymphomas, directly into the CSF. Through this procedure, Dr. Rubenstein is able to circumvent the blood-
brain barrier, and deliver a relatively large drug (>140 kDa) to the brain, something not easily possible from the blood.
While Dr. Rubenstein presented a powerful case for Rituximab delivery via the CSF, he also mentioned the limits of this treatment. While delivering Rituximab is possible, the drug is cleared from the brain within hours of treatment, requiring repeated administration. In addition, this treatment is limited; patients were found to build resistance to Rituximab over time. It is clear that there is still work to be done to optimize CSF drug delivery, as well as optimize drugs for function in the immunologically privileged brain.
by Peyton Shieh
Prof. James Rubenstein spoke today on “Drug Delivery to the Central Nervous System”. He is a physician-scientist at UCSF interested in delivering biologics and triggering immune responses that target brain cancer. One in six Americans suffer from some sort of brain-related disease, from Alzheimer’s to lymphoma to depression. Unfortunately, the blood-brain barrier represents a major barrier, in the literal sense, to the development of pharmaceuticals for the treatment of these diseases. The blood-brain barrier only allows relatively small, lipophilic drugs to access the brain from the bloodstream. For brain cancer, this means that potent chemotherapeutics like Taxol or biologics like Rituximab are rendered ineffective. A way to circumvent this barrier is the direct injection of active pharmaceutical agents into cerebrospinal fluid (CSF) to access the brain. To perform CSF-delivery, Prof. Rubenstein uses the Ommaya reservoir, a plastic pipette-like device that is connected to a metal catheter. This device is surgically implanted into the patient’s skull, with direct access to the lateral ventricles of the brain, major reservoirs of CSF. Prof. Rubenstein has shown that CSF-delivery can be successful in the treatment of brain lymphomas using the biologic Rituximab, yet further optimization of this strategy is still needed. One major limitation is that compounds delivered in the CSF have a very short resident half-
life, less than four hours, although the reasons behind this rapid clearance are not clear. A better understanding of the mechanisms of clearance, however, may allow for the optimization of therapeutics for CSF-delivery. Alternatively, this short half-life may be overcome through the use of a pump to continuously inject the drug into the patient using the Ommaya reservoir. While Prof. Rubenstein focused mostly on CSF-delivery, he briefly discussed other strategies for bypassing the blood-brain barrier. I found one strategy, using a hyperosmotic agent such as mannitol to bust through the blood-brain barrier, particularly interesting given its non-invasive nature. Mannitol non-selectively permeabilizes the blood-brain barrier, which can lead to side effects such as seizures or strokes. Designing a smarter hyperosmotic agent using the tools and strategies we’ve learned in our chemical biology course may allow for more selective permeabilization of this barrier to minimize the risk of side effects.
By Ioannis Mountziaris
The field of chemical biology has developed a broad toolset for the development of new therapeutics. Our expanding knowledge of biological mechanisms led to the identification of novel drug targets and the development of new drug candidates. But to bring the discoveries from the academic and industrial labs to patients, the drug must pass through FDA clinical trials, at medical schools such as UCSF.
During his recent talk, Dr. Rahul Aggarwal, an Assistant Clinical Professor at UCSF, focused on answering how drug candidates undergo phase I clinical trials. With the limited number of patients available for drug trials, a significant amount of in vitro and in vivo evidence is required from research scientists, including the pharmacodynamics, drug targets, and mechanism of action. Only upon passing FDA vetting can a clinical trial begin, with the first interest being the determination of the range of doses possible for the drug in question, with a determination of efficacy of the drug a bonus. The average phase I trial has less than twenty patients, limiting the number of samples available to test and time period for safe and effective dose determination. The most surprising aspect of clinical trials is their codependence on both academics, to execute the study, and industry, which are the primary financiers of drug testing. This relationship is a philosophical and legal minefield, where researchers and doctors have to weigh their relationships with their patients with the desires to develop new and effective drugs.
Have you been looking at grant announcements lately? Than you know translational science is a hot area for funders right now. Get inspired for up and coming research opportunities here! CBGP students who have attended translational talks will post what they learned from doctors who spoke about areas in their fields where they wish more basic research was available.