The first phase of Project Violet is focusing on cancer, healthy aging (e.g., preventing stroke), brain and mental health disorders, and a certain type of autism. The nature of this research enables it to be applied to so many more diseases as well, including rare diseases. Below are just some of the current focuses of Project Violet.
The Optides research can be potentially applied to many cancers. Currently, the research is targeted towards the following cancers: Brainstem Glioma, Glioblastoma Multiform (GBM), Atypical Teratoid Rhabdoid Tumors (ATRT), Primitive Neuroectodermal Tumors (PNET), Medulloblastoma, Melanoma, Triple Negative Breast Cancer, Sarcoma. Below are more detailed descriptions of the research of some of these cancers.
[The visual above shows sections of a brain with tumor; the purple portions represents where the tumor is located.]
Glioblastoma Multiform (GBM)
Glioblastoma Multiform (GBM) is a fast-growing type of central nervous system tumor that forms from glial (supportive) tissue of the brain and spinal cord. Children with GBM have a 5 year survival rate of less than 10%. To identify new therapeutic targets, we discovered a method for evaluating whether each gene in the genome specifically kills cancer cells while sparing normal neural stem cells. We identified a number of targets that are differentially necessary for the survival/growth of the cancer but not normal cells. We are now looking to interrogate these targets for therapeutic potential, specifically whether we can find an Optide or small molecule that could inhibit one of these targets in a cancer specific manner. If we are successful in finding an effective peptide or molecule, potentially it could also be used for treating other cancer types because of the associated mutations driving the susceptibility of these cancer cells.
Metastatic Colon Cancer
Colorectal cancer (CRC) is the fourth most common cancer and is the second leading cause of cancer-related mortality. One of the reasons why it has such a high mortality rate is that it frequently metastasizes, which means that the cancer cells develop the ability to move away from their original site and form a tumor in a new location in the body. Metastatic tumors are often difficult to detect, due to their small size and potentially wide distribution throughout the body, and they are difficult to treat since they have often acquired mutations that make them resistant to standard-of-care chemotherapeutics.
The CRC cells express a tumor-specific marker, called guanylyl cyclase c (GCC), a protein that is universally expressed by both primary and metastatic CRC cells. When the metastatic cells move outside of the gastrointestinal tract, GCC acts as a specific marker for them because it is not expressed on normal tissues anywhere else in the body.
The Project Violet team is exploring the possibility of developing an Optide that binds specifically to GCC on metastatic CRC cells. This Optide can be conjugated to a chemotherapy drug and thereby specifically deliver the drug to the cancer cells, without causing harm to the normal tissues in the body. Interestingly, there is a well-known toxin that has a cysteine-knot conformation and binds to GCC. Therefore, we can use structural information from this toxin to help us design an Optide that will bind to GCC and deliver a drug to the tumor cells. This Optide drug could serve as a much-needed effective therapeutic for metastatic CRC patients.
Soft-tissue sarcomas are a collection of cancers that form in connective tissue (such as muscle, fat, etc.). Early-stage tumors are highly treatable by surgery, but as soon as they begin to spread the 5-year survival drops to 10-20%. These metastatic sarcomas are resistant to nearly all currently available therapies.
In some early experiments of Project Violet, the Optide Team tested the ability of a peptide from locusts to accumulate in sarcomas by using a fluorescent dye to track the molecule. Excitingly, it appeared to accumulate to a greater degree in the tumor than other tissues. We are exploring ways to increase the amount of this Optide that gets into tumors by changing the structure of the peptide.
The Team is hoping to use this molecule as a way to deliver chemotherapy specifically to sarcomas cells that have spread throughout the body and treat cancer that is otherwise resistant to therapy. This could fill a pressing need for patients with metastatic soft-tissue sarcoma.
Brain/Nerve degeneration affects millions of Americans. They all impact a person’s everyday life, from the ability to move around freely to their memory and problem solving capabilities. All these diseases are progressive, as parts of the brain or spine will degenerate over time. Some of these diseases run in families to various degrees, while other cases are triggered through less well-known means. The Project Violet team is exploring potential applications of their Optides for these diseases.
These diseases are good candidates for targeting using Optides because they're associated with protein misfolding. When proteins fold properly, they go to their proper site in the cell and generally go about their business. But when they do not fold properly (sometimes due to normal aging, sometimes due to a genetic variant of the protein), the proteins can end up in unusual places inside or outside the cell. Misfolded protein are not doing their proper job, and they can stick to other proteins which prevents those other proteins from accomplishing their normal functions as well. Misfolded proteins can even make the immune system think that an infection is taking place, causing a chronic inflammatory response.
The Project Violet team hopes to identify Optides that can bind to, and affect the folding of, certain proteins that are prone to misfolding in neurodegerative diseases (click here for an illustration of this). Their Optides may be ideally suited for such endeavors because they are large enough to participate in and affect protein-protein interactions, but they are small enough to enter the brain from the bloodstream.
Some of the specific neurodegenerative diseases that the lab is working on include Huntington's Disease, Alzheimer's Disease, and Parkinson's Disease.