By Dr. Gail M. Seigel, Laboratory of Ocular and Auditory Neuroscience, in collaboration with Dr. Dhavalkumar Shah, Department of Pharmaceutical Sciences, University at Buffalo.
The research
Our retinoblastoma (Rb) research group at the University at Buffalo is working on new and improved drug therapies for retinoblastoma. As with all treatments for Rb, our goals are to:
- preserve the life of the patient,
- preserve vision, and
- minimize the side-effects of treatment.
Chemotherapy has become the treatment of choice for Rb in recent years, mainly to preserve the eye and visual function. Yet, the most commonly used chemotherapeutic drugs are not specifically developed for Rb and can have unwanted side effects. Our research addresses an urgent medical need to develop new anticancer drugs specifically developed for Rb that can preserve vision and minimize side effects.
During our CHECT funding period, we have made significant progress in the development of targeted ADCs for Rb. For one, we have manufactured and analysed new, more powerful ADCs and demonstrated that these drugs effectively kill retinoblastoma cells.
The drugs that we are developing are called ADCs (antibody-drug conjugates). ADCs are designed to specifically kill retinoblastoma tumour cells while sparing normal surrounding cells. ADCs have several advantages over current chemotherapy drugs. Because the ADC is very small in size and is delivered directly to the tumour, it exists in a small area around the tumour itself. This lessens the chance of negative side effects throughout the body. Also, since ADCs remain intact at the site of the tumour longer than other kinds of drugs, fewer doses need to be administered to the patient. Therefore, targeted ADCs will not only provide a better treatment option for Rb patients with improved potency and safety, it will also be more convenient.
In addition, we have successfully added a green fluorescent label onto retinoblastoma cells as a way to clearly see these cells using our new retinal imaging system. By observing the growth of green fluorescent Rb tumours in the laboratory, we can see the effect of our ADCs on the growth of Rb tumours over a long period of time. This retinal imaging system also makes it easier for us to take samples from the eye to measure how much ADC remains after the drug is administered. Once we know how long the active ADC remains in the eye after treatment, it will help us calculate how often the drug should be given for maximum effect.
This is a retinoblastoma tumour that shows our drug target HER2 (seen as green fluorescence). The ADC drugs that we developed will find the HER2 on the cell surface, attach to it, and then are actively brought inside the cell where they release a toxic molecule that kills the cell from the inside.
One other important aspect of the ADC is the target. The target is a marker, or landmark, on the surface of the Rb tumour cell that is unique to Rb and not present on surrounding normal tissues. The target allows the ADC to find the tumour cell and stick to it. Once the ADC sticks to the tumour cell, it is swallowed by the cell and detonates a toxic molecule that kills the cell from the inside. This is a very precise and elegant method of killing just the tumour cell and not the surrounding normal cells. As you can imagine, the target(s) we choose are very important.
For this study, we have looked at two targets, called HER2 and EpCAM. Part of our study was to see how many Rb patient samples have enough of this target for the ADC to be effective. The answer is that many, but not all Rb tumours have HER2 and EpCAM targets. We also check to see whether normal cells adjacent to the tumour might have these targets, which could cause the ADC to kill them unintentionally. For these reasons, we are always on the lookout for new targets on Rb tumours so that we can develop personalized treatments to benefit the maximum number of Rb patients.
The University at Buffalo retinoblastoma research group alongside our retinal imaging system. From left: Dr. David Bussing, postdoctoral fellow; Dr. Gail M. Seigel, Principal Investigator; Dr. Dhaval Shah, Co-Principal Investigator.
We are excited to report that we have leveraged the support from CHECT to obtain additional funding from the Developmental Studies Hybridoma Bank at the University of Iowa so that we can identify new targets on the surface of Rb cells for potential ADC therapies. So, as you can see, our Rb research continues thanks to you, the many supporters of CHECT. For that, we are very grateful.
Read more about our research
If you want to read more technical details about our research, please feel free to read our latest CHECT supported work. We presented our work at the annual Association for Research in Vision and Ophthalmology conference in Vancouver, Canada in May 2019 in a “hot topic” poster session. The abstract was entitled, “Her2 RNA expression in retinoblastoma and adjacent retina detected by in situ hybridization”.
Our work has also been accepted for peer-reviewed publication [Seigel, Shah, Mendoza, Mendoz, Szalai, Grossniklaus, Song and Shan, In situ analysis of Her2 DNA and RNA in retinoblastoma and adjacent retina, Oncoscience in press, 2019].