Veronesi Lab

The Veronesi Lab

There are many different projects currently underway at the Veronesi Lab, but overall they investigate the use of high powered imaging modalities (such as MRI and PET scans) along with chemotherapy and potential surgery to help combat glioblastomas (a type of brain cancer). Glioblastomas (GBMs) are typically resistant to certain immunotherapies due to extra-cellular conditions created by the tumor, but some immunotherapies (like the use of natural killer cells) can help to combat cancers more effectively than certain chemotherapies. The Veronesi Lab is currently trying to determine how long the natural killer cells are present around the tumor by putting a radioactive tracer on them and using PET scans to measure. Another project currently underway at the Veronesi Lab is the use of nanoparticles to treat the glioblastoma. When taken traditionally, the medicine combination to treat the glioblastoma is filtered out by the blood brain barrier, which overall reduces the effectiveness of the drugs. By encapsulating them in nanoparticles, the drugs are able to pass through the blood brain barrier and to the glioblastoma. PET scans are then used to identify the effectiveness of this medicine delivery route, and the lab is currently working on developing radiotracers that are longer-lasting to help map where the nanoparticles end up in the brain. In addition to this, the Veronesi Lab is working on developing a way to verify if medicines are reaching the glioblastoma with immunosuppression brought on by the glioblastoma. There are two different specific antigens present on a glioblastoma that the medicines target, and by adding radiotracers to the nanoparticles, PET scans can be used to identify where the medicine ends up once in the brain. The final major project that the Veronesi Lab is working on is targeting the glioblastoma's stem cells which are highly resistant to chemotherapies. The drug combinations used in the projects mentioned above work to target these stem cells, but the success of the chemotherapy depends on the route of administration of the drugs. Again, PET scans are used to determine the effectiveness of the administration of the drug in the subject. The lab maintains cell cultures in-vivo (immunodeficient rats) and in-vitro. The majority of the in-vivo studies are done to model the effects that these therapies might have on human subjects.

My specific role in this is to help culture the GBM cells, run in-vitro drug trials, and to develop an in-vivo model (rats) that can be used for the drug trials. By helping to culture the GBM cells and run in vitro drug trials, I am hoping to gain the basics of cell culturing and scientific research. With the development of in vivo models that are used for in vivo drug trials, my hopes are to continue to develop and understand the basic skills and knowledge required for scientific research, and I hope to acquire and improve surgical skills and techniques for GBM implantation that will eventually help me on my way throughout medical school on my route to eventually become a surgeon.

An example of the surgical implantation of cells and a cannula similar to the work of the Veronesi Lab is shown below. (WARNING: THIS VIDEO CONTAINS LIVE IMAGES OF SURGERY BEING PERFORMED ON RODENTS. WATCH AT YOUR OWN DISCRETION.)

jove-20-880.mp4

(Source: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3233859/)

The basal ganglia is the target area for cellular implantation. To reach this, an atlas of the rats brain given in stereotactic coordinates was used to determine the proper location without interfering with the primary motor cortex of the rodent. These images are shown below using: Paxinos, George, and Charles Watson. The rat brain in stereotaxic coordinates: hard cover edition. Access Online via Elsevier, 2006.

This image is used as a reference to show the different cross sections of the brain. This will help to give perspective to the cross section shown below of the injection point for the GBM cells. (Source: https://www.researchgate.net/figure/Different-planes-of-MRI-brain-image_fig1_312024048)

The red dot shows the approximate location of cellular injection in the rat's brain. The defining point of Bregma was used to locate this. The cells were injected into the caudate putamen which is a large area of the basal ganglia responsible for coordinating voluntary movement, learning, reward, motivation, movement, and emotion.

This dorsal view of the skull highlights Bregma's Point. Bregma's point is the union of the coronal sutures of the skull and the anterior and posterior midsagittal sutures of the skull. (Sourced from: http://play.psych.mun.ca/~smilway/landmarks.html)

In my experiences volunteering and shadowing physicians, I have been able to see how high powered imaging modalities have been used to diagnose and treat patients without need for major surgeries. In addition to this, I have been fascinated with nervous system, specifically since some of my close family members deal with neurological issues. The electro-chemical function of the nervous system is incredibly fascinating to me, and I believe that my background in chemistry helps me to understand both the anatomy and the physiology behind why the nervous system behaves in the ways that it does. Even with the minimally invasive imaging modalities used, surgeries still will need to be preformed on the rodents used in lab, and I believe that performing some of these procedures will give me a unique skill set s i desire to be a surgeon in the future. In addition to that, the skills I obtain from working behind the scenes participating in research to better patient care, treatment, and outlook will be extremely useful as I gain more experience and eventually hope to join the medical field.

Projects While in the Lab:

Development and Characterization of a Novel Preclinical Brain Tumor Model (4/19/21)

Luke R. Jackson, Michael C. Veronesi

Glioblastoma multiforme (GBM) is a highly malignant brain tumor with a poor prognosis despite aggressive surgery and radiochemotherapy options. The current standard of care treatment fails the vast majority of patients because of the highly resistant and infiltrative nature of GBM. Therefore, preclinical research is vital for developing novel therapies that cannot yet be tested in humans. In addition, brain tumor imaging is complex and new diagnostic imaging approaches are needed to distinguish tumor from treatment related non-tumor changes. To address these challenges, the goal of this research project was to develop a novel preclinical brain tumor model using a recently developed immunodeficient transgenic rat intracranially implanted with human glioblastoma cells. Full model characterization would eventually include clinical, imaging, and histologic validation and optimization. The rat GBM model would be the first of its kind offering important advantages for development of novel therapies assessed in vivo with hybrid positron emission tomography and magnetic resonance imaging (PET/MRI).

Development of a novel preclinical brain tumor model for in vivo drug testing (7/31/21)

Luke R. Jackson, Megan R. Masi, Michael C. Veronesi

Glioblastoma multiforme (GBM) is a highly malignant brain tumor with a poor prognosis despite aggressive surgery and radiochemotherapeutic options. The current standard of care treatment fails the vast majority of patients because of the highly resistant and infiltrative nature of GBM. Therefore, preclinical research is vital for developing novel therapies that cannot yet be tested in humans. In addition, brain tumor imaging is complex and new diagnostic imaging approaches are needed to distinguish between progressing tumor and treatment related non-tumor changes. To address these challenges, development and optimization of a transgenic immunodeficient rat will continue through varying the location, concentration and amount of human derived GBM cells during intracranial implants. In the second half of the project, initial therapeutic response will be tested with standard of care chemotherapy agent coupled with in vivo imaging characterization. Further imaging incorporates a clinical need for personalized medicine and more accurate therapy assessment earlier on. Bioluminescence imaging will be utilized as well as simultaneous positron emission tomography and magnetic resonance imaging to further optimize the brain tumor location and degree of invasion/malignancy. In this set of experiments, the effects of the temozolomide will be examined and eventually other synergistic drugs (paclitaxel and RG7388) on U87 tumor growth in the Rag2-Null Sprague Dawley Rat (Synergism source). The current project will contribute to the long-term goal of the research laboratory of integrating preclinical models of GBM for therapy and imaging testing for eventual translation to the clinic and for personalized medicine.

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