Five teams led by Weill Cornell Medicine scientists have been awarded funding from the Starr Cancer Consortium in its 16th annual grant competition. The grants will fund research on the molecular origins and evolution of blood, bladder, breast, and colon cancers.
The Starr Cancer Consortium was established in 2006 through the philanthropy of the Starr Foundation, and includes The Broad Institute of MIT and Harvard, Cold Spring Harbor Laboratory, Memorial Sloan Kettering Cancer Center, The Rockefeller University and Weill Cornell Medicine. The goal of the consortium is to support collaborative research at these institutions, with the potential to transform the understanding and treatment of cancers.
“Collaboration is at the heart of the Meyer Cancer Center. As we learn through studying various innovative treatment modalities, and with interdisciplinary engagement, we can see similarities between diseases and apply therapies more broadly. This award will help us move the needle on cancer diagnosis and care for the benefit of patients in our catchment area and globally," said Dr. Jedd Wolchok, the Meyer Director of the Sandra and Edward Meyer Cancer Center at Weill Cornell Medicine. "We are so grateful to the Starr Foundation for its generous support.”
Collaborative projects proposed by Drs. Steven Josefowicz, Dawid Nowak, Melody Zeng, Lukas Dow and Bishoy Faltas were selected for funding by a scientific review board of peers from institutions outside the consortium.
“We are grateful for the generosity of the Starr Foundation, which supports these ambitious efforts to advance cancer research and patient care,” said Dr. Hugh Hemmings, senior associate dean for research and chair of the Department of Anesthesiology at Weill Cornell Medicine. “We are very proud to see such strong support by the Starr Foundation this year for Weill Cornell Medicine investigators’ projects.”
Dr. Steven Josefowicz
Associate Professor of Pathology and Laboratory Medicine
Mechanisms of dynamic chromatin reorganization regulating B-cell differentiation and lymphomagenesis (renewal of prior award)
In response to an infection, some B cells, which make antibodies, go through a phase of hyper-mutation and proliferation. The purpose of this process, which takes place in a lymph node region called the germinal center, is to boost the diversity of the antibodies that can bind to the invading pathogen, making the response more effective. But this process also puts B cells on the brink of turning cancerous, and indeed many lymphomas arise from germinal center B cells, apparently due to a failure of normal regulatory systems in these cells. Dr. Josefowicz and colleagues are pursuing the hypothesis that one of these failures is akin to a stuck gas pedal for a pathway involving the phosphorylation of DNA packaging histones called histones, a process that potently activates genes controlling growth and lymphomagenesis—and that blocking this process with the right drugs could send some aggressive lymphomas into swift remission.
Co-Principal Investigators: Dr. Christina Leslie (Memorial Sloan Kettering Cancer Center), Dr. Ari Melnick (Weill Cornell Medicine) and Dr. Shixin Liu (The Rockefeller University).
Dr. Dawid Nowak
Assistant Professor of Pharmacology in Medicine
Determining and targeting evolutionary trajectories driving bladder cancer
Muscle-invasive bladder cancer (MIBC), so-called because it has invaded the bladder muscle, is difficult to treat successfully. The dearth of good treatments is due to the relatively poor scientific understanding of how MIBC arises. Dr. Nowak and his team are trying to improve this understanding with the help of a new, sophisticated model of MIBC in mice. Tumors in the model are driven by genetic mutations frequently observed in human MIBC, and can recapitulate metastasis to lymph nodes, all in mice with intact immune systems. The model also employs a DNA “evolving barcode” for the detailed tracking of MIBC evolution. The researchers will use the mice to generate ideas for new treatments, and ultimately to test those treatments.
Co-Principal Investigators: Dr. David Solit (Memorial Sloan Kettering Cancer Center) and Dr. Adam Siepel (Cold Spring Harbor Laboratory).
Dr. Melody Zeng
Assistant Professor of Immunology in Pediatrics
Defining the role of stress-induced changes in the IgG-gut microbiome-neutrophil axis during breast cancer progression and metastasis
Dr. Zeng and her collaborators are studying interactions/crosstalk between IgG-type antibodies, white blood cells called neutrophils, and bacteria that dwell in the human gut that could promote cancer and its spread to distant organs. The researchers have found evidence that chronic stress, a deficiency of IgG antibodies, and/or the presence of certain gut bacteria, can perturb this signaling axis in a way that leads to immune suppression and cancer progression in mouse models of cancer, including breast cancers. They expect to translate their novel findings into new treatment strategies for breast cancer, potentially including vaccines against specific gut bacteria.
Co-Principal Investigators: Dr. Irina Matei (Weill Cornell Medicine) and Dr. Mikala Egeblad (Cold Spring Harbor Laboratory).
Dr. Lukas Dow
Associate Professor of Biochemistry in Medicine
Identifying acquired vulnerabilities driven by lineage plasticity and drug resistance in CRC
Traditionally, research on the mechanisms of cancer progression has focused on new DNA mutations in cancer cells as key sources of enhanced malignancy. But cancer biologists increasingly recognize that non-mutational mechanisms controlling the patterns of gene activity in cells are also to blame, including proliferative mechanisms that are normally seen only in the fetal stage of life, or in wound healing. In this project, Dr. Dow and his collaborators will examine some of these mechanisms and their roles and interactions—and vulnerabilities—in colorectal cancer treatment resistance and metastasis.
Co-Principal Investigator: Dr. Karuna Ganesh (Memorial Sloan Kettering Cancer Center)
Dr. Bishoy Faltas
Assistant Professor of Cell and Developmental Biology; Director of Bladder Cancer Research at the Caryl and Israel Englander Institute for Precision Medicine; and a member of the Sandra and Edward Meyer Cancer Center
Targeting cytidine deaminase-induced chromosomal instability as a driver of metastasis in bladder cancer
APOBEC3 enzymes, which are produced widely in human cells, have the curious property that they induce mutations in DNA. This is at least in part to defend against infecting retroviruses, such as HIV, and cells are thought to have safety mechanisms for protecting their chromosomal DNA from these enzymes. However, Dr. Faltas and other researchers have been finding evidence in recent years that these enzymes are co-opted by some cancers, including bladder cancers, to boost their mutation rates—making it easier for them to evolve. In this project, they will explore APOBEC3s’ roles in driving bladder tumor metastasis, as well as the possibility of targeting these enzymes to prevent metastasis.
Co-Principal Investigators: Dr. Samuel Bakhoum (Memorial Sloan Kettering Cancer Center) and Dr. Vivek Mittal (Weill Cornell Medicine).