Innovative Research Grants 2011
SU2C's newest Innovative Research Grant recipients were awarded on April 4th, 2011. This second round of high-risk, high-reward IRG grants support cutting-edge cancer research from early-career scientists who might not receive funding through traditional channels. Take a look at the novel ideas presented by this year's 13 recipients and find out how their projects have a strong potential to impact patient care.
IRG Recipients at a Glance
Targeting MLL in Acute Myeloid Leukemia
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. 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 AML are mostly cytotoxins and yield disappointing results with less than 20 percent of AML patients surviving after five years of treatment. The goal of Dr. Dou’s research is to identify a whole new class of drugs for AML that specifically target the tumor initiating cells. Dr. Dou believes this is very promising research that, to date, has not been pursued in a highly focused and coordinated way. Toward this goal, she plans to collaborate with other investigators with diverse expertise to develop compounds to target the enzyme that in humans is encoded by the mixed-lineage leukemia (MLL) gene. The goal of Dr. Dou’s proposed research is to further develop these and other drug candidates for AML so that they may move rapidly into clinical testing.
“You have to believe in what you are doing and you have to go through phases of frustration, knowing that one day if it's to prevail, it's going to be very good.”
Targeting Genetic and Metabolic Networks in T-ALL
T-lineage acute lymphoblastic leukemia (T-ALL) is an aggressive hematologic malignancy that requires treatment with intensified chemotherapy. Despite recent progress in the treatment of this disease, 25 percent of children and 40 percent of adults with T-ALL show primary resistant leukemia, 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 drugs.
This project will identify key genes that are essential for the proliferation and survival of T-ALL cells. To achieve this goal, Dr. Ferrando will use emerging technologies to compile a complete catalog of genetic alterations responsible for the pathogenesis of T-ALL to analyze how these mutations impact the circuitries that control normal cell growth, proliferation and survival. He will also analyze the effects of cancer mutations in the complex and intricate circuitries that control leukemia cell proliferation and survival. This T-ALL network represents a roadmap of how T-ALL mutations work, and how they interact with each other and 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.
“We all appreciate that the boldest and most innovative projects are the ones that drive the field forward in a technological and conceptual way. The speed of development that we are seeing in science today is unprecedented. It’s very exciting.”
Targeting Protein Quality Control for Cancer Therapy
The normal growth and proliferation of cells is orchestrated by a cascade of events that are initiated by the binding of a stimulus to a receptor at the 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. Current drugs bind to these growth receptors at the membrane. However, drug resistance can develop over time.
Recently, 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. Dr. Jacinto found that mTORC2 also controls growth receptors, such as epidermal growth factor receptor. Dr. Jacinto will examine this novel function of mTORC2 in regulating epidermal growth factor receptor expression and quality control. Inhibiting mTORC2 in cancer would prevent cell survival and blocking the expression of epidermal growth factor receptor before it reaches the cell membrane, thereby preventing growth of cancer cells. Dr. Jacinto will use cell and mouse models to inhibit mTORC2 in breast cancer cells.
This could have implications in a number of cancer types, and ultimately reveal new modes of therapy for breast cancer and other malignancies.
“The most inspiring thing for me is knowing that what we’re doing can help people.”
Targeting PP2A and the Glutamine-Sensing Pathway as Cancer Treatment
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 and glucose are two major nutrients that support cancer cell growth and survival. This project will 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 cancer cells. However, all these drugs have to be used at a high dose, resulting in toxic side effects. Thus, sensitizing cancer cells to these drugs by blocking cell survival mechanisms is necessary to inhibit tumor growth. Dr. Kong will test the idea that we can starve cancers to death 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 will potentially benefit a large population of cancer patients.
“Stand Up To Cancer provides unique opportunities and lets us run instead of walk, because cancer patients cannot wait. I think everyone has his or her own responsibility to society. My responsibility is to cure cancer.”
Chimeric RNAs Generated by Trans-Splicing and their Implications in Cancer
Genetic information flows from DNA to messenger RNA, and then to protein. In cancer, one of the hallmarks is DNA rearrangement, which results in the fusion of two separate genes. These gene fusion products often play critical roles in cancer development.
Traditionally, they are thought to be the sole product of DNA rearrangement, but Dr. Li recently discovered another mechanism that could generate the same fusion product without DNA rearrangement. This process is called “RNA transfusion RNA, which then is translated into a fusion protein. Dr. Li’s goal is to understand the physiological functions of the RNA trans-splicing process and its implications in cancer. He will identify examples of trans-spliced RNAs in normal and cancer cells, and validate the 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.
“It is a promising time in cancer research because of the advances in technology, the information explosion, and new concepts being developed in cancer research. I think the puzzle pieces are there. We just need to put them together.”
Exome Sequencing of Melanomas with Acquired Resistance to BRAF Inhibitors
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 as well as 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 undesirable side effects.
A small molecule (PLX4032) targeting a common melanoma mutation, V600EB-RAF, is showing unprecedented promise in advanced stages of clinical trials (80 percent 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 will study tissues derived from clinical trial patients. He will enlarge this tissue collection by collaborating among distinct clinical trial sites. Finally, because finding a specific mechanism among the myriad of cancer-related changes is akin to finding a needle in a haystack, he should capitalize on the latest, “high-throughput” genomic technologies. By harnessing the speed of “next-generation” DNA sequencing technology, he will examine 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.
“In cancer research today we’re experiencing accelerated discovery, so now is the time to use the most powerful scientific tools and to recruit the greatest talents. Our research is out of the box in the sense that we’re applying the latest technology to a problem that’s never been examined this way before.”
Identification and Targeting of Novel Rearrangements in High-Risk ALL
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 recent preliminary studies have used new genetic techniques to analyze leukemic cells obtained from children with ALL at high risk of relapse. This has identified new genetic changes that are 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.
This project will determine the nature and frequency of these novel genetic alterations in ALL in children and young adults, and will use cutting-edge genomic profiling approaches to identify new genetic alterations in high-risk ALL. Dr. Mullighan will go on to develop experimental models that mimic human ALL in order to determine how these changes cause leukemia, in order to enable testing of new targeted therapies.
“There's enormous intellectual satisfaction about taking a problem that we don't understand and trying to create new knowledge.”
A Systems Approach to Understanding Tumor Specific Drug Response
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 are the information processing devices of cells. In cancer, these networks go awry in various ways, arming the cancer with the ability to abnormally grow, metastasize and evade drugs. Treatment that is based on understanding which components go wrong, and also how these go wrong in each individual patient, will improve cancer therapeutics. Dr. Pe’er will use genomic technologies to track how tumors respond to potent drug inhibition of critical pathways. She will develop cutting-edge computational machine learning algorithms to piece these data together and illuminate 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 will begin to piece together general principles and patterns in drug responses.
These studies should show what drives cancers and what part of the networks should be targeted for treatment. For each individual patient, she will determine the best drug regime, informed by a model that can predict how the tumor will respond to drugs and drug combinations.
“We have the tools to do what we couldn't do before. Tools that we couldn't have even thought or dreamt of having to really study cancer, understand cancer, and figure out what can kill it. I think we’re in the most incredible, and hopeful time for cancer research.”
Targeting Sleeping Cancer Cells
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 proven 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 will use 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 kill them while they sleep.
“I think it’s critical to be continually pushing the envelope. To the degree that one tries new things, you have a better chance of finding new things.”
Inhibiting Innate Resistance to Chemotherapy in Lung Cancer Stem Cells
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” (growing flat on the plates).
Research over the last decade has demonstrated that this method of culturing cells is very different from the conditions that tumor cells experience in a patient. Sweet-Cordero has developed an approach that incorporates the advantages of mouse models and “3D” culture systems to study cancer, and will use 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. Alejandro will carry out a screen using a technology called “shRNA,” which allows him to selectively inhibit the action of individual genes. He will test 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 to treat human lung cancer.
“Innovative proposals sometimes are great ideas, but don't have all of the background data to support them; and in order for them to move forward, they require the funding from forward thinking, innovative groups such as Stand Up 2 Cancer.”
Developing New Therapeutic Strategies for Soft-tissue Sarcoma
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 will die from their disease. Dr. Wagers’ 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 introduces into these cells specific genetic modifications associated with human sarcomas.
Using this model, she 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 will evaluate a library of drugs that target her identified sarcoma-associated genes, and identify those that prevent or impede sarcoma development, growth or metastasis. These efforts will benefit from synergistic analyses in her established mouse model and an entirely new, humanized system that will allow her to interrogate the efficacy of candidate therapeutics in an appropriate human cell context.
This approach will generate essential pre-clinical data to facilitate clinical translation of candidate pharmaceutical targets identified and validated by our studies. 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.
“Science is all about discovery, and you can only discover things by coming at it in a new way. We need to approach cancer in every creative way that we possibly can because this is a terribly important problem.”
Framing Therapeutic Opportunities in Tumor-activated Gametogenic Programs
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 only normally required for reproduction and not otherwise expressed in an adult lung, heart, brain, etc. 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 found in tumors but not in normal adult tissues. Dr. Whitehurst will use a unique large-scale approach to determine which of these genes are most critical for tumor cell survival. Next, she will test if they are required for survival in tumors in animals. Finally, because little is known about how they support growth of tumor cells, she will investigate 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.
“We have more knowledge than we’ve ever had before, and knowledge is power. Cancer isn’t getting smarter, but we are.”
Coupled Genetic and Functional Dissection of Chronic Lymphocytic Leukemia
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 patient tumors to chemotherapy. There is a need for improved understanding of how disease starts and progresses, which would lead to better predictive markers and potentially more effective (and non-toxic) 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. She is examining how genes are expressed in the same patient tumors using gene microarrays. Dr. Wu’s 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 will use 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 will determine which genes are good predictors of disease progression. Then, she will use nanowires to place the mutant genes from CLL tumors into normal B cells and see how they affect their behavior. This project will lead to an understanding of the basic reasons why CLL patients develop cancer. The information will help predict progression of disease and provide new strategies for therapy. Her approach can be extended to other tumors, especially leukemias and lymphomas.
“I think advocating for getting novel findings and translating it earlier to the clinic is imperative.”
Meet the Innovative Research Grants 2011 Recipients
- Targeting MLL in Acute Myeloid Leukemia
- Targeting Genetic and Metabolic Networks in T-ALL
- Targeting Protein Quality Control for Cancer Therapy
- Targeting PP2A and the Glutamine-Sensing Pathway as Cancer Treatment
- Chimeric RNAs Generated by Trans-Splicing and their Implications in Cancer
- Exome Sequencing of Melanomas with Acquired Resistance to BRAF Inhibitors
- Identification and Targeting of Novel Rearrangements in High-Risk ALL
- A Systems Approach to Understanding Tumor Specific Drug Response
- Targeting Sleeping Cancer Cells
- Inhibiting Innate Resistance to Chemotherapy in Lung Cancer Stem Cells
- Developing New Therapeutic Strategies for Soft-tissue Sarcoma
- Framing Therapeutic Opportunities in Tumor-activated Gametogenic Programs
- Coupled Genetic and Functional Dissection of Chronic Lymphocytic Leukemia