Healthy cells are unable to survive outside their original niche, but during cancer progression, malignant cells acquire the ability to adapt to foreign environments. This property of adaptability, or “plasticity,” is possible because tumors are able to change over time niche they find when they spread to different organs. A similar adaptation process can occur when tumor cells are treated with drugs; although at first the drug may work against the tumor, internal processes in the cancer cells change to make them more resistant to therapy. The goal of this project is to better understand the fundamental internal processes of plasticity in cancer cells, so that we can find better ways to defeat metastases and drug resistance.

While it is unclear how tumor cells perform the internal reconfigurations needed for adaptation, it is known that biochemical pathways that specialize in transmitting messages within the cell and controlling gene expression are involved. The Albeck lab has developed an imaging technique that allows these messaging pathways to be monitored continuously in living cells, providing a new window onto how cells decide which genes to turn on or off. The hypothesis is that random periods of gene activity intensify as the cellular environment changes during tumor progression, allowing some tumor cells to activate genetic programs that give them a survival advantage. Albeck is testing this hypothesis by combining his lab’s novel imaging technology with a cell culture system that mimics different points in a tumor’s progression. Cellular survival in response to chemotherapy will be tracked, as will the random changes that provide cells with temporary resistance to drugs. By tracking the underlying diversity of evolving tumor cell populations and focusing on the most drug-resistant cells, the researchers hope to identify new treatment strategies that are more effective and have fewer side effects.

Changes in DNA, known as mutations, can arise during cancer and in some cases are also a cause of cancer. Every day, our DNA is damaged from internal sources (such as free radicals) and external sources (such as ultraviolet light or radiation), and damaged DNA can lead to mutations. In healthy cells, many proteins work together to repair DNA damage as it arises. One of the most toxic types of DNA damage a cell can encounter is called a DNA double-strand break (DSB); just one unrepaired DSB will result in cell death. Cells have specialized proteins that work to fix DSBs. The repair process can stop working, however, if the DNA repair proteins are themselves mutated. Mutations in DNA repair pathways have been linked to a number of human cancers. This study focuses on a group of DSB repair proteins known as the RAD51 paralogs, which have been linked to cancer susceptibility, particularly in breast and ovarian cancers. There are five RAD51 paralogs that work to repair broken DNA and maintain the health of a cell. The goals of this project are to 1) understand the importance of the RAD51 paralogs in repairing DSBs; 2) understand why people who have mutations in any one of the RAD51 paralogs are more likely to develop cancer; and 3) determine novel methods for treating RAD51 paralog-mutant cancers. The ultimate goal is to uncover individualized cancer treatments for these particular tumors to ensure that patients will have the best outcomes.

In 2016, it is estimated that more than 22,000 American women were diagnosed with ovarian cancer and more than 14,000 died from the disease. Novel and more effective therapeutic strategies are urgently needed in the clinic to improve the dismal prognosis of this devastating disease. A form of immunotherapy, adoptive T-cell therapy, utilizes immune cells called T cells that are engineered in the laboratory to recognize and eliminate cancer cells. This type of immunotherapy has been used successfully in melanoma patients but has had only partial success in treating ovarian cancer. This is thought to be because the ovarian tumor microenvironment—the cells and structures that surround and support the cancer cells—work to suppress T-cell activity. Preliminary evidence from the Cubillos-Ruiz group has confirmed that dendritic cells, another type of immune cell that is common in the tumor environment, are programmed in such a way that they inhibit T cell function. Cubillos-Ruiz’s research aims to understand how dendritic cell signaling is altered in ovarian cancer tumors. Specifically, he is investigating a novel immunosuppressive pathway driven by a unique class of molecules, called lipid messengers, in the dendritic cells of the tumor environment. The hypothesis is that these lipids cause severe immune cell dysfunction that limits the clinical benefit of adoptive cell therapy in ovarian cancer. Therefore, this research aims to determine if blocking the activity of these immunoregulatory lipids could provide a new approach to improve the effectiveness of ovarian cancer immunotherapies.

The past several years have brought considerable progress to the field of immunotherapy, the goal of which is to stimulate and amplify a patient’s own immune response to recognize and destroy tumor cells. Despite the remarkable success of immunotherapy in some forms of cancer, many tumors do not respond because the cancer cells change their surrounding environment, termed the tumor microenvironment, so that it restricts immune cell function. For example, tumor cells use molecules called immune checkpoints to suppress anticancer immune function. In addition, tumor cells consume a lot of fuel to continue to grow, evolve, and metastasize. In so doing, they effectively starve the microenvironment and incoming immune cells of the energy they need to carry out their antitumor functions. This research focuses on two immunotherapy approaches that have proved successful, using viruses that specifically infect and destroy tumor cells (oncolytic viruses), and drugs that inhibit immune checkpoints, thereby releasing the inhibition on immune cell function. The goal is to improve and combine the use of oncolytic viruses with immune checkpoint inhibitors to achieve a more potent immune response. First, Delgoffe and his team are engineering cancer-specific viruses so that they specifically target and destroy tumor cells; they are also working to reprogram the low-nutrient immune-suppressive conditions of the tumor microenvironment with the hope of enabling immune cells to function properly. The next step is to combine the oncolytic viruses with drugs that inhibit an immune checkpoint called PD-1 to see if the combination produces a magnified effect. These new, metabolism-targeting viruses, alone and in combination with checkpoint inhibitors, will be tested against melanoma in laboratory mice with the hope of bringing these new therapeutic approaches to patients in the future.

All cells must balance the amount of protein they produce with the amount of protein they discard. Cells use robust systems to maintain this balance, termed “protein homeostasis” or “proteostasis.” Cancer cells divide rapidly and tend to accumulate genetic changes that result in mutated proteins. It is thought that this higher burden of mutated proteins makes cancer cells unusually dependent on the cellular systems that maintain proteostasis. Drugs that partially disrupt proteostasis have transformed patient care in some types of cancer, such as multiple myeloma. However, less than 1% of the factors within proteostasis pathways have been explored as possible targets for cancer therapeutics, providing many possible opportunities to develop new cancer drugs targeted to these pathways. This study uses cutting-edge genomics methods, coupled with dedicated drug discovery methods, to identify and validate the next generation of drug targets in the proteostasis network in multiple myeloma, castration-resistant prostate cancer, and aggressive forms of these diseases. Kampmann has pioneered a new genomic approach to rapidly identify the “weak points” in cancer cell proteostasis. The ultimate goals of this study are to create a genetic map of alterations in the dynamic proteostasis network and to develop drugs that target those pathways as new cancer therapeutics.

Within a single tumor there are multiple cancer cell subtypes. This diversity means that tumors can “try out” different ways to overcome the effects of anticancer drugs and reemerge as a more aggressive form of the disease. Thus, despite striking initial responses to therapy, the malignancy often evolves and adapts, leading to recurrence. Combination therapies can block the ability of the cancer to evolve around any single therapy, but deciding on which drugs to combine, and how to combine them, is a major challenge. This project is focused on a new mathematical approach in designing combination therapy for chronic lymphocytic leukemia (CLL). The investigators are proceeding by two routes: First, they are genetically engineering CLL cells to recreate the diversity of cancer cell subtypes seen in tumors in order to determine which subpopulations are resistant to treatment with single agents or a combination of agents. Second, the investigators are screening for genetic differences in CLL cells taken from patients before and during therapy to characterize how cells respond differently to drugs, either administered to the patients or used in laboratory experiments. The measurements from these experiments will enable advanced mathematical models of leukemia growth, taking into account the fact that each cell subpopulation within the leukemia responds differently to different drugs. These data-driven models are expected to generate and optimize patient-specific combination treatment plans.

A growing number of oncoproteins (proteins that promote tumor growth) and pro-metastatic proteins (proteins that promote the spread of tumor cells from the original tumor site/organ) have been extensively characterized. However, many of these cancer-promoting proteins have not themselves been targeted for development of new drugs. There is a need, therefore, for alternative therapeutic strategies directed toward cancer-promoting proteins. Much attention has been paid to a small protein called ubiquitin, which is found in almost all tissues and serves as a tag that helps signal to cells how to regulate other proteins. Enzymes called deubiquitinating enzymes, or DUBs, remove ubiquitin from proteins, thereby modifying function. The hypothesis in this research is that DUBs substantially regulate key cancer proteins and pathways, thereby promoting tumor cell growth and metastases. Although DUBs have not previously been considered as good candidates for drug development, Ma hypothesizes that some types of ubiquitins can be targeted to treat cancer. In humans there are 79 DUBs, providing a wealth of possible drug targets. Researchers are working to identify and target DUBs so as to inactivate some key oncoproteins or pro-metastatic proteins, either by destabilizing them or by changing their activity. Ma’s laboratory has already identified the first DUB that suppresses tumors by regulating the key anticancer protein, PTEN. In this study, Ma is screening a library of DUBs for those that regulate key oncoproteins and pro-metastatic proteins. In parallel, she will determine which DUBs promote tumorigenesis, metastasis, or therapy resistance. The identified cancer-promoting DUBs will be tested for their ability to serve as anticancer targets, paving the way for development of DUB inhibitors as new cancer drugs.

Cancer is a complex disease that includes distinct groups of cells that are in the same tumor but react differently to treatment. This cell-to-cell diversity, or tumor heterogeneity, makes it difficult to eliminate all tumor cells because most drug combinations fail to kill a minority population of resistant tumor cells. These resistant cells then grow and metastasize, resulting in recurrence of the disease in a more aggressive, drug-resistant form. Pancreatic ductal adenocarcinoma (PDAC), which has a dismal five-year survival rate of only 7%, is one of the most heterogeneous cancers, resulting in significant treatment resistance. Drug development for PDAC is significantly behind that of other cancers, with no effective targeted drugs on the market. Standard-of-care chemotherapies for PDAC exhibit varying degrees of toxicity and effectiveness, and there is no rational system to match each patient with the least toxic and most effective drugs for his or her tumor. New approaches are needed to improve the care of cancer patients through new drug development, rational treatment planning, and reduced toxicities. The goal of this research is to address these gaps in drug development and treatment planning in PDAC by directly measuring how different subtypes of cells within the same tumor respond to drugs. Scala and her team are extracting patient tumor samples and growing them in specialized conditions to create tumor organoids (tumors in a dish) in the laboratory. Using a new imaging technology, they are assessing individual cells for drug responses while they are still growing side by side in a tumor organoid, mimicking what happens in a real tumor. The tumor organoid drug response data is then being compared with data for real tumors taken from patients undergoing drug treatment before surgery so that this single-cell assessment technique can be validated as a way to measure heterogeneous drug responses in human PDAC. This novel approach to examine drug effects in heterogeneous tumors holds great promise for rational, personalized drug development and treatment planning.

Tumor cells require nutrients to survive and grow. These nutrients are provided by the cells that surround the tumor—the tumor microenvironment. Understanding the aspects of metabolism that are essential for tumor growth may reveal how best to exploit altered cancer metabolism and thereby identify targets for new drugs and improved cancer treatment. Vander Heiden is researching the fate of different nutrients within tumors. First, he is tracing specially labeled nutrients within a tumor to understand the differences in nutrient metabolism in laboratory models of lung, pancreatic, and prostate cancers, compared with normal cells. Next, he is genetically deleting enzymes important for cellular metabolism from the laboratory models to determine which enzymes are critical for tumor initiation and maintenance. Last, existing therapies directed toward key to targets in the metabolic pathway are being tested to preferentially inhibit cancer growth. The overall goals of this research are to define the metabolic dependencies of lung, pancreatic, and prostate cancer, to determine how best to use existing drugs targeting metabolism, and how to combine these drugs with new approaches to treat patients.

In mammals, there is a strong association of cancer with chronic damage to the skin, intestine, and liver. The connection is complicated, however, because the regenerative abilities of these organs serve to protect tissue integrity, reduce inflammation, and resist cancer formation during injury. Zhu’s work focuses on a gene called Arid1a, which has been associated with cancer. Zhu has found that genetic deletion of Arid1a profoundly increases the healing capacity of the liver after injury without increased cancer. Indeed, deletion of this gene in laboratory mice actually protects the animals against liver cancer. Zhu’s new research aims to understand the relationship between injury, regeneration, and cancer and more specifically to investigate Arid1a and its related biological pathways as new therapeutic targets. The idea is that blocking regeneration-suppressing genes like Arid1a will promote tissue regeneration and prevent or delay carcinogenesis. Using laboratory mice that are engineered to lack the Arid1a gene, Zhu’s lab is examining whether changing the regenerative capability of injured livers and colons influences cancer formation. They are also investigating how a regenerating tissue influences nearby tumor cells in tissue. Finally, they are performing a genetic screen on their laboratory mice to identify factors that influence Arid1a-associated tissue regeneration and determine how Arid1a may be connected with cancer.