The human body’s immune system is a powerful weapon against cancer, but cancer can also create a complex environment that weakens immune system effectiveness. This environment, called the tumor microenvironment (TME), is made up of different cell types, including tumor cells and immune cells. Scientists have discovered a protein called STING that can change the TME and activate the immune system to fight cancer. However, STING therapy hasn’t worked well in clinical trials because tumors have become resistant to it. To activate STING, researchers use a small molecule called cGAMP. Treatment of cancer with cGAMP can activate STING in various cell types within the TME. When cGAMP is delivered to most immune cells in the TME, it activates STING and triggers an immune response against cancer. However, we found that cGAMP can also be delivered to T cells, which are important cells in killing cancer cells, it actually causes T cells to die. This weakens the immune system’s ability to fight cancer. Therefore, we think that the entry of cGAMP into T cells leads to their death, allowing tumor cells to escape being killed by T cells. Our goal is to identify the specific molecules responsible for cGAMP entry into T cells and develop new strategies to overcome tumor resistance to STING therapy by blocking the entry of cGAMP into T cells.

One major challenge in treating any type of cancer is resistance, or when a cancer stops responding to a certain type of drug or therapy. Some cancer cells may become resistant by changing the way they read and write their DNA, or the genetic blueprint in the cell nucleus. Other cells may change the way proteins are expressed on the surface, which can change their shape or ‘stickiness’ and ability to move in the body.  When doctors can understand exactly how cancer cells become resistant to a certain drug, they can sometimes combine two or more drugs together to overcome this.

For some new classes of drugs, we have not even begun to explore how cancer cells might become resistant. One of these classes is nanoparticle drugs, which usually involves bringing together molecules like fats or polymers to help delivery drugs into certain cells. The goal of this research project is to identify the ways that pediatric cancer cells can become resistant to nanoparticle drugs, and find new drug combinations that are more effective and less toxic to children with cancer. Many lab-based studies of nanoparticles are performed in common cancers of adulthood such as breast cancer, and this has led to new treatments in the clinic, but there have been very few studies of nanoparticle drugs in childhood cancer. Currently, there is only one nanoparticle drug approved for use in children. By studying resistance to nanoparticle drugs in a deadly childhood brain tumor, we can take the first step towards a new clinical treatment for these children.

Scientists learned how glioblastoma grows in its tumor microenvironment (TME) in the brain using a receptor called PTPRZ1.  Findings show that the GBM tumor is aggressive in hijacking cells outside of the original tumor creating a growing tumor.  In learning how GBM grows, scientists are learning why it is aggressive, how it grows so quickly, how the tumor reacts within the entire brain, how to better understand how to treat it with the PTPRZ1 receptor.   Understanding how the tumor grows and mutates is critical for surgery, treatment, and drug interaction with the tumor. 

Most cancer treatments — such as chemotherapy, radiation therapy and targeted therapy — work by direct killing of cancer cells. Some of the recent and most powerful therapies work by stimulating the patient’s own immune system to kill cancer cells. While these new immune-based therapies work better than most previous therapies and are now approved for treating 13 cancer types, they do not work for all patients. To understand why these treatments work for some patients and not others, we need better tools to investigate how the immune system interacts with cancer. We have developed a new way of growing tumors outside patients’ bodies to study how tumor cells and immune cells interact with each other. This research aims to study how different types of immune cells stop cancer growth, using tumors grown outside of the body to test new treatments designed to steer the immune response towards tumor cells more effectively. If initial tests are successful, we will aim to try these new treatments in patients with melanoma and potentially other types of cancer.

The results of these studies are expected to lead to combination strategies that can be explored clinically in patients resistant to immunotherapy. The resulting work with these scientists is advancing this therapy to the clinic and combination clinical trials with anti-CD38 therapeutics.

Currently, 50-65% of patients with advanced melanoma are resistant to current treatment strategies. Scientists have profiled explants in an effort to understand diverse individuals and tumors.  Doing this in the future with trials will potentially impact dozens of individuals as part of early-phase testing. Hundreds of patients with advanced melanoma not responding to cancer immunotherapy could be impacted by the successful development of novel treatment approaches.

The Duke Cancer Institute and the College of Veterinary Medicine at N.C. State University formed a Comparative Oncology Consortium (COC), taking advantage of their expertise and national leadership in their respective disciplines. This collaborative pre-clinical and clinical cancer research advanced our understanding of both cancer causation (a high incidence of specific cancers in specific dog breeds) and of behaviors and genetics of specific tumor types, as well as to coordinating clinical trials in humans and canines so that novel therapies can be tested in both settings, with information gained in one setting informing the other. The ability to use biomarkers and pharmacology in the canine models can be a novel addition to the characterization of these new cancer therapies and these insights could result in significant enhancements of clinical trial designs including dosing, scheduling, and combination therapies when these treatments are tested in human clinical trials. Cost savings and improved clinical trials encourage pharmaceutical companies to use the canine models as part of the assessment process, benefiting canine patients by giving them access to these novel therapies.

Immunotherapy has emerged as a powerful approach to treating cancer, but only a subset of patients respond, and the remainder suffer severe side effects without benefiting from the therapy. There is a critical need to understand the limiting factors in immunotherapy's success and develop strategies to enhance responsiveness. Most immunotherapies involve the killing of tumor cells by immune system cells called T-cells. For T-cells to attack tumors, the tumors must have a protein called MHC on their surface. 

This work focuses on immunotherapy for medulloblastoma (MB), the most common malignant brain tumor in children. A mutation was recently identified in the study of organoids that leads to the loss of MHC on MB cells, making tumors that carry this mutation invisible to T-cells and insensitive to many immunotherapy approaches. It is unknown whether this same mutation causes loss of MHC in human MB - if so, patients with this mutation might be unresponsive to immunotherapy. Importantly, research also identified proteins that can restore MHC expression in tumor cells carrying the mutation.

This study hypothesizes that these proteins could be used in conjunction with immunotherapy to turn on expression of MHC and render tumors more sensitive to T-cell attack. If successful, the work proposed here will pave the way toward more effective use of immunotherapy for patients with MB and other pediatric cancers.