Acute myeloid leukemia (AML) is a form of cancer in which the normal development of blood cells is blocked and the cells multiply abnormally. AML affects children and adults, with about 12,000 new U.S. patients each year according to 2010 estimates. A substantial portion of AML cases have extremely poor prognosis.

Although considerable progress has been made in understanding the causes of AML, the drugs currently used to treat it are mostly cytotoxins that yield disappointing results: Less than 20 percent of AML patients survive after five years of treatment. The goal of this research is to identify a whole new class of drugs for AML that specifically target tumor-initiating cells. Toward this goal, she is collaborating with other investigators with diverse expertise to develop compounds targeting the enzyme that in humans is encoded by the mixed-lineage leukemia (MLL) gene. Dr. Dou hopes to further develop these and other drug candidates for AML so that they may move rapidly into clinical testing.

T-lineage acute lymphoblastic leukemia (T-ALL) is an aggressive hematologic malignancy that requires treatment with unusually strong chemotherapy. Despite recent progress in the treatment of this disease, 25% of children and 40% of adults with T-ALL are either unresponsive or respond only transiently to chemotherapy and ultimately fail to be cured. Further treatment advances require the development of effective and highly specific molecularly targeted therapies.

The aim of this project is to identify key genes that are essential for the proliferation and survival of T-ALL cells. To achieve this goal, Dr. Ferrando is using emerging technologies to compile a complete catalog of genetic alterations responsible for the pathogenesis of T-ALL in order to analyze how these mutations impact the complex and intricate circuitries that control leukemia cell growth, proliferation, and survival. This T-ALL network, essentially a road map of how T-ALL mutations work and how they interact with one another, will facilitate the identification of key genes and pathways. Selective inhibition of these genes will identify targets for the development of new, more active, and highly specific anti-leukemic drugs.

This project represents a unique opportunity to exploit genomic technologies and develop new approaches to identify targeted therapies that will ultimately be applicable to a broad spectrum of cancers.

The normal growth and proliferation of cells are orchestrated by a cascade of events initiated by the binding of a stimulus to a receptor at the cell membrane. Once triggered, the receptor communicates to the rest of the cell via recruitment of a number of signaling molecules. In cancer, the alteration of growth or survival signals can ultimately cause the signaling circuits to go out of control. Abnormal changes in receptor levels generate more cell changes that lead to uncontrolled growth. Most cancer therapy takes advantage of this phenomenon with drugs that bind to these growth receptors at the membrane. However, drug resistance can develop over time.

Dr. Jacinto discovered that a protein complex, mTORC2, which is known for its function in activating the protein Akt, has a crucial role in protein production and quality control. She found that mTORC2 also controls growth receptors, such as epidermal growth factor receptor. Dr. Jacinto is examining this novel function of mTORC2 in regulating epidermal growth factor receptor expression and quality control. Inhibiting mTORC2 in cancer would prevent cell survival, blocking the expression of epidermal growth factor receptor before it reaches the cell membrane, thereby preventing growth of cancer cells. Dr. Jacinto is using cell and mouse models to inhibit mTORC2 in breast cancer cells.

This research could have implications in a number of cancer types and ultimately reveal new modes of therapy for breast cancer and other malignancies.

Normal body cells grow, divide, and die in an orderly fashion. Cancer arises if cells in a particular tissue begin to grow out of control. Most fast-growing cancer cells acquire mutations enabling them to take in more nutrients from the environment in order to divide. However, rapid tumor growth often leads to nutrient deprivation conditions in tumor cells. Cancer cells develop strategies to survive a low-nutrient environment. Understanding these mechanisms is important for developing new drugs that could starve tumor cells to death and block cancer progression.

Glutamine is a major nutrient that supports cancer cell growth and survival in some cancer types. This project attempts to determine the molecular basis of tumor cell survival under glutamine deprivation in order to develop novel drugs targeting this pathway. To date, drugs designed to inhibit cancer cells from using nutrients have been successful in killing those cells. However, all these drugs have to be used at a high dose, resulting in toxic side effects. Therefore, sensitizing cancer cells to these drugs by blocking cell survival mechanisms is necessary to inhibit tumor growth. Dr. Kong is testing the idea that we can starve cancers by blocking the nutrient supply and PP2A, which is a phosphatase that plays a critical role in mediating cell survival upon glutamine deprivation.

If successful, this strategy is likely to be applicable to numerous tumor types, and therefore this research has the potential to benefit a large population of cancer patients.

Genetic information flows from DNA to messenger RNA, and then to protein. One of the hallmarks of cancer is DNA rearrangement, which results in the fusion of two separate genes. Traditionally, it was thought that these gene fusion products, which often play critical roles in cancer development, were created solely by DNA rearrangement. But Dr. Li discovered another mechanism that could generate the same fusion product without DNA rearrangement. Dr. Li’s goal is to understand the physiological functions of the RNA trans-splicing process and its implications in cancer. He is identifying examples of trans-spliced RNAs in normal cells and cancer cells and validating potential therapeutic candidates identified through these approaches. Stem cell differentiation could shed light on the cells of origin for some mysterious cancers.

Because of the broadness of gene fusions in cancer, Dr. Li’s discovery has already raised concerns for false positive cancer diagnoses with current diagnostic methods, as well as for potential side effects in normal tissues caused by therapies targeting these fusion protein products. Dr. Li hopes to better characterize the trans-splicing process and translate this knowledge into better diagnostic and therapeutic approaches.

Cutaneous melanoma ranks among the fastest-rising human malignancies in annual incidence and is highly lethal when detected at advanced stages. Standard chemotherapy often targets fast-dividing cells, in both the tumor and some normal tissues of the patient, giving rise to unwanted side effects. Targeting a specific feature of cancer not present in the normal cells would reduce these side effects.

A small molecule (PLX4032) targeting a common melanoma mutation, V600EB-RAF, is showing unprecedented promise in advanced stages of clinical trials—80% of patients respond if their tumors harbor the V600EB-RAF mutation—but drug resistance occurs over time and leads to clinical relapse. Dr. Lo reported in Nature the discovery of two means by which melanomas escape from PLX4032, which suggest new treatment strategies that are testable in clinical trials. Discovering mechanisms of acquired PLX4032 resistance is logically the first step in constructing a therapeutic strategy closer to a cure.

Dr. Lo is studying tissues derived from clinical trial patients and enlarging this tissue collection by collaborating among distinct clinical trial sites. Because finding a specific mechanism among the myriad of cancer-related changes is akin to finding a needle in a haystack, he is capitalizing on “high-throughput” genomic technologies. By harnessing the speed of next-generation DNA sequencing technology, he is examining the protein-coding regions of the melanoma genomes for key genetic alterations that account for acquired resistance. This effort will inform clinical trials and will help guide patient care.

Acute lymphoblastic leukemia (ALL) is the most common childhood cancer and the leading cause of nontraumatic death in children and young adults. Until recently, the reasons why some people respond poorly to treatment have not been understood. Dr. Mullighan’s preliminary studies have used new genetic techniques to analyze leukemic cells obtained from children with ALL at high risk of relapse. This work has identified new genetic changes associated with treatment failure, including alterations of the gene IKZF1, and previously unidentified chromosomal changes that activate genes that drive the proliferation of leukemic cells. These altered genes include ABL1, CRLF2, JAK2, and PDGFRB. These genes may be targeted by specific drugs, suggesting that patients with these alterations may be treated with these agents.

In this project, Dr. Mullighan is working to determine the nature and frequency of these novel genetic alterations in ALL in children and young adults and using cutting-edge genomic profiling approaches to identify new genetic alterations in high-risk ALL. The experimental models mimicking ALL that he is developing will shed light on how these genetic changes cause leukemia, enabling the testing of new targeted therapies.

Cancer is an individual disease—unique in how it develops and behaves in each patient. The emergence of revolutionary genomic technologies, combined with increased understanding of the molecular basis underlying cancer initiation, has increased the hope that treatment will improve by becoming more targeted and individualized in nature.

Dr. Pe’er’s project elucidates tumor-specific molecular networks, which inappropriately tell a cell to grow and divide. In cancer, these networks go awry in various ways, arming the cancer with the ability to abnormally grow, metastasize, and evade drugs. Treatments based on understanding which components go wrong, and how these go wrong in each individual patient, will improve cancer therapeutics. Dr. Pe’er is using genomic technologies to track how tumors respond to potent drug inhibition of critical pathways. Further, she is developing cutting-edge computational machine learning algorithms to piece these data together, illuminating how a cell’s regulatory network processes signals and how this signal processing goes awry in cancer. By utilizing a large panel of diverse tumors in this study, she is then piecing together general principles and patterns in drug responses.

These studies are showing what drives cancers and what part of the networks should be targeted for treatment, helping Dr. Pe’er determine the best drug regime for each individual patient, informed by a model that can predict how the tumor will respond to drugs and drug combinations.

Cancer cells of different types have the very strange ability to go to sleep and then eventually wake up. While cancer cells sleep, they are resistant to virtually all currently available forms of treatment. However, we do not understand how highly aggressive cancer cells become dormant. It has proved extremely difficult to study these cells directly in patients, and we have lacked suitable model systems to study them in the laboratory.

Dr. Ramaswamy recently made a remarkable observation that has the potential to open this important area for new investigation. He found that highly aggressive cancer cell lines of various types occasionally produce dormant cells. This has enabled the development of methods to identify, isolate, and experimentally probe spontaneously arising quiescent cancer cells at the molecular level. Dr. Ramaswamy is using cutting-edge genomic, proteomic, and computational technologies to identify and validate genetic and protein signaling networks that trigger and maintain cancer cell dormancy. His goal is to develop new diagnostics and drugs based on this insight to prevent cancer cells from becoming dormant or to kill them while they sleep.

Lung cancer is projected to remain a leading cause of cancer death for the foreseeable future. The most common form of lung cancer is non-small cell lung cancer (NSCLC). Platinum-based chemotherapy drugs are commonly used to treat NSCLC and other cancers, though treatment with these drugs has limited effect. There is a need to develop new ways to increase the effectiveness of chemotherapy for this disease. Current strategies for developing new drugs for NSCLC rely almost exclusively on testing of candidate agents on established cell lines. A limitation of working with cell lines is that they are usually grown directly on plastic culture dishes in “2D” (that is, in two dimensions, growing flat on the plates).

Research over the past decade has demonstrated that this method of culturing cells creates conditions very different from those that tumor cells experience in a patient. Dr. Sweet-Cordero has developed an approach that incorporates the advantages of mouse models and “3D” culture systems to study cancer and is using this approach as a platform to identify new ways to make chemotherapy more effective at killing lung tumor cells. Using tumor cells isolated from a well-characterized mouse model of lung cancer in which tumors carry one of the most frequent genetic mutations found in human lung cancer, a gene called Kras, Dr. Sweet-Cordero is carrying out a screen using a technology called “RNA interface” (RNAi), which allows him to selectively inhibit the action of individual genes. He is testing whether loss of specific genes makes cells growing in 3D more sensitive to chemotherapy. His studies will result in the identification of new targets for drugs that make chemotherapy more effective in treating human lung cancer.

Sarcomas are highly aggressive cancers that arise in connective tissues such as bone, fat, and cartilage, as well as in muscles and blood vessels embedded within these tissues. Approximately 12,000 Americans are diagnosed with sarcoma each year. These tumors can occur at any age, but many (e.g., rhabdomyosarcoma) are disproportionately common in children and young adults.

Current sarcoma treatment strategies are often ineffective, particularly with advanced disease, and sadly, even with the most advanced therapies currently available, one-third to one-half of sarcoma patients die from their disease. Dr. Wagers’s lab has developed a novel mouse model of soft-tissue sarcoma in skeletal muscle. This model exploits her lab’s unique ability to isolate discrete subsets of tissue stem cells found normally in the skeletal muscle and the connective tissue surrounding it, and to introduce into these cells specific genetic modifications associated with human sarcomas.

Using this model, Dr. Wagers found that introduction of a particular combination of modifications into distinct types of tissue stem cells rapidly and reproducibly generates transplantable sarcomas that model particular subtypes of human tumors. By comparing these different tumors, she has identified a small group of genes present at increased levels in both mouse and human sarcomas.

Dr. Wagers hypothesizes that this novel set of sarcoma-induced genes includes new candidate drug targets. She is evaluating a library of drugs that target her identified sarcoma-associated genes and identifying those that prevent or impede sarcoma development, growth, or metastasis. These efforts benefit from synergistic analyses in her established mouse model and an entirely new, humanized system that allows her to interrogate the efficacy of candidate therapeutics in an appropriate human cell context.

This approach is generating essential preclinical data to facilitate clinical translation of candidate pharmaceutical targets identified and validated by Dr. Wagers’s research. Ultimately, this work will identify new, more effective anti-sarcoma therapies based on a better understanding of how these cancers arise and grow, provide new insights into the root causes of sarcoma formation, and identify new strategies to cure these aggressive cancers.

Unlike infectious diseases, cancer is caused by a rewiring of normal molecular systems to produce an uncontrollably dividing cell. This characteristic makes it notoriously difficult to identify therapeutic mechanisms that will target cancer cells without harming normal tissues.

Tumors, at high frequency, turn on genes that are normally required only for reproduction and not otherwise expressed in an adult lung, heart, brain, and so on. If these genes are necessary for tumor cells to survive, they present a tremendous opportunity as therapeutic targets, since they are not required for the function of critical organs. Dr. Whitehurst’s group studies whether the proteins encoded by these genes are required for tumor cells to grow and divide. Her work has revealed that directly inhibiting a subset of these proteins can lead to the selective death of cancer cells, thereby providing a previously unrecognized basis for the design of new cancer therapeutics. Her lab’s mission is to build and expand on this expertise to more broadly evaluate all 105 of the genes that are inappropriately exposed in tumors but not in normal adult tissues. Dr. Whitehurst is using a unique, large-scale approach to determine which of these proteins are most critical for tumor cell survival, then testing to see if they are required for survival of tumors in animals. Finally, because little is known about how they support growth of tumor cells, she is investigating the ways in which they interact with other proteins to promote the unbridled growth of tumor cells. Ultimately, this work will present new targets for therapeutic intervention that will selectively destroy tumor cells and leave normal tissues unharmed

There are two main challenges to treating chronic lymphocytic leukemia (CLL): predicting the clinical course in a disease that shows many differences across patients, and overcoming the insensitivity of some patients’ tumors to chemotherapy. There is a need for improved understanding of how the disease starts and progresses, which would lead to better predictive markers and potentially more effective (and nontoxic) therapies.

Recent advances in genomic technologies provide a unique opportunity to find the genes and molecular circuits that make tumors grow in CLL. Dr. Wu is sequencing genes from tumor and normal cells from CLL patients and examining how genes are expressed in the same patient tumors using gene microarrays. Her laboratory pioneered the use of silicon-coated nanowires as a method of delivering DNA and RNA to primary CLL and normal B cells, allowing her to genetically manipulate CLL cells for the first time in a high-throughput fashion. Her analysis thus far has identified genes important for CLL, and the nanowires have verified the importance of some of these genes in CLL tumor cells. This project enables Wu to find all the major genes and pathways that control CLL tumor formation. She is using a combination of sequencing technologies with statistical analyses to find the key genes that are important in creating tumors in CLL patients.

In addition, she is determining which genes are good predictors of disease progression, then using nanowires to place the mutant genes from CLL tumors into normal B cells to see how they affect their behavior. This project will lead to an understanding of the basic reasons why CLL patients develop cancer. This information will help predict progression of the disease and provide new strategies for therapy. Her approach can be extended to other tumors, especially leukemias and lymphomas.