Explore this Laboratory
Welcome to the Cusack Laboratory at Massachusetts General Hospital. Our focus is translational research that advances the understanding of cancer treatment resistance mechanisms through the development of novel targeted therapies in order to improve patient survival. Findings from the Cusack Laboratory have shown that conventional anti-cancer therapies, such as radiation and chemotherapy, induce resistance mechanisms under the control of the gene transcription factor NF-kappaB. Blocking these responses with targeted therapies augments the effectiveness of anti-cancer therapies.
In the field of molecular therapeutics, our two most cited papers describe the inhibition of the transcription factor NF-kappaB to overcome inducible chemotherapy resistance:
- “Control of inducible chemoresistance: Enhanced anti-tumor therapy through increased apoptosis by inhibition of NF-kappaB,” from Nature Medicine 1999
- “Enhanced chemosensitivity to CPT-11 with proteasome inhibitor PS-341: implications for systemic nuclear factor-kappaB inhibition,” from Cancer Research 2001
Lab principal investigator James C. Cusack, MD, is co-inventor of the patent “Use of NF-kappaB inhibition in combination therapy for cancer,” (United States patent 6,831,057), which describes the therapeutic strategy noted above and is now licensed to two pharmaceutical companies for novel drug development.
Dr. Cusack wrote the first clinical trial of combination chemotherapy with the drug bortezomib for solid organ malignancies, reported in the journal Cancer. With our recent discovery of the molecule HB-EGF in resistance pathways, we worked with collaborators in Japan to bring a new drug to the clinic that targets this specific pathway.
Dr. Cusack organized the Mass General Peritoneal Surface Malignancy Program in 2011 and treated his first patient with cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) in October, 2011. This program was launched in collaboration with colleagues in medical oncology to promote a better understanding of peritoneal carcinomatosis and to develop a platform for experimental therapeutics for improving outcomes for patients. A range of research projects both clinical and preclinical are currently underway.
Our investigations are ongoing in biomarkers of resistance and potential new targets for therapeutic intervention in colorectal cancer, melanoma and Merkel cell carcinoma. The Cusack Laboratory has been funded since 1995 by the National Institutes of Health, American Cancer Society, American College of Surgeons Oncology Group, biotechnology collaborators and contributions from Dr. Cusack’s patients.
Targeting XPO1 (exportin) to overcome resistance to BRAF inhibition in melanoma
- James C. Cusack, Jr., MD
- Keith Flaherty, MD
- Ryan Sullivan, MD
- Isabel Ferreiro, PhD
- Roberto Salas, MD
Karyopharm Pharmaceuticals, Inc.
Protein transport between the nuclear and the cytoplasmic compartment is a key factor for cell viability and proliferation. The fact that XPO1 and other essential nucleo-cytoplasmatic transport proteins are over expressed in cancer, specifically in melanoma, offers the opportunity to treat cancer by modulating this transport system. Novel selective inhibitors of nuclear export (SINE) have achieved outstanding preclinical results and are currently in Phase I trials. SINE analogs target XPO1-mediated nuclear export and affect the localization and function of fundamental proteins for melanoma survival, proliferation and resistance to therapy. In preclinical studies performed in our laboratory, the addition of XPO1 to BRAF inhibitor–based therapy synergistically decreases melanoma proliferation and enhances apoptosis induction, resulting in complete tumor regression in BRAF mutant melanoma. These findings suggest a role for XPO1 inhibition as a tool to prevent and overcome resistance to current BRAF-inhibitor therapy.
Our study will be the first-in-melanoma use of SINE analogs for the treatment of patients with BRAF inhibitor–resistant melanoma in an attempt to overcome resistance and improve patient outcomes in a Phase I/II trial setting. In addition, we plan to apply the concept of systems biology to elucidate not only mechanisms of resistance to BRAF inhibitors, but also the role that XPO1 inhibition plays in overcoming and enhancing BRAF therapy. A systems biology approach will further increase our understanding of melanoma, potentially identifying biomarkers and novel targets for melanoma treatment. We propose a single-arm, Phase I/II trial that combines KPT-330 and vemurafenib (PLX4032) in patients with V600–mutated metastatic melanoma.
Protein transport between the nucleus and the cytoplasm is important for cell maintenance, cell proliferation and cell survival. Alterations in the expression of nuclear-transport-related proteins, in particular Exportin 1 (or XPO1, also known as Chromosome Region 1, CRM1), are common in melanoma and other cancers, such as colon and rectal cancer, and are linked to inactivation of tumor suppressor proteins, apoptosis evasion and resistance to chemotherapy. We have shown that novel selective inhibitors of nuclear export (SINE), known as KPT–analogs (KPT-185, KPT-251, KPT-276, and KPT-330), are capable of binding to the Cys-528 residue in the cargo-binding portion of the XPO1 protein, successfully preventing protein transport from the nucleus to the cytoplasm in colon cancer cell lines. In combination with chemotherapy agents in colon cancer and other malignancies, modulation of the XPO1 function using this SINE has achieved promising preclinical results and is currently in Phase I clinical trial.
Clinical grade SINE (KPT-330) is currently in Phase I clinical trial. Thus far, KPT-330 is very well tolerated and has demonstrated no significant side effects at tested doses. Changes in nuclear localization of p53 and other transcription factors have been correlated to KPT-330 treatment in the treated population. We are currently evaluating the use of KPT-330 to enhance radiation sensitivity in pre-clinical colorectal cancer models. In addition, studies are underway to identify the underlying mechanism of response to KPT inhibitors.
Promoting chemotherapy-induced apoptosis in a model of peritoneal carcinomatosis
NPI-0052 treatment induces cell cycle arrest in colon cancer cells during mitosis. A novel proteasome inhibitor NPI-0052 had no effect on the formation of mitotic spindle or centrosomes. We found that treatment of the colon cancer cells with a novel proteasome inhibitor permitted the chromosomes to align on the cell equator, but the cells fail to enter anaphase resulting in cell cycle arrest. Image at right: magnified view showing chromosomes aligning on the cell equator.
- James C. Cusack, Jr., MD
- David Ryan, MD
- Jason Faris, MD
- Janet Murphy, MD
- Carlos Chan, MD, PhD
- Isabel Ferreiro, PhD
- Zhi Fong, MD
- Teresa Kim, MD
The genotoxic effect of conventional anti-cancer therapy, involving many chemotherapy agents and gamma irradiation, results in the induction of apoptosis in cancer cells. The ability to inhibit apoptosis appears to be a principal mechanism by which resistant cancer cells are protected from chemotherapy and radiation. Cellular mechanisms that protect cancer cells against apoptosis include lack of a functional response mechanism to apoptotic stimuli (e.g., mutated or deleted p53 tumor suppressor gene), presence of an inhibitor to apoptosis (e.g., Bcl-2, IAP), and the expression of the multi-drug-resistance gene (MDR). Recently, we found that the inducible activation of the nuclear transcription factor NF-kappaB inhibits the apoptotic response to chemotherapy and irradiation. NF-kappaB, a key transcription factor for immune and inflammatory responses as well as cell growth, is regulated primarily through interactions with the inhibitor protein IkappaB. Stimuli that activate NF-kappaB typically induce the recently identified IkappaB kinase (IKK) to phosphorylate IkappaB on N-terminal serines, leading to ubiquitination and subsequent degradation of the inhibitor by the proteasome. Following IkappaB degradation, NF-kappaB translocates to the nucleus, where it regulates genes involved in a range of processes, including the suppression of apoptosis.
We previously described a gene therapy approach that uses a recombinant adenovirus to transfer a modified form of IkappaBalpha. In these experiments, transfer of super-repressor IkappaBalpha resulted in significant augmentation of chemosensitivity and enhanced induction of apoptosis in a xenograft tumor model in response to chemotherapy treatment. These findings suggest that NF-kappaB represents an important molecular target for the purpose of enhancing the sensitivity of certain cancer cells to apoptotic stimuli. The use of gene therapy to deliver NF-kappaB inhibitors is relevant to certain cancers but limited when considering widely disseminated metastases.
An alternative strategy for the inhibition of NF-kappaB activation is facilitated by inhibition of proteasome function. The inhibition of proteolytic function effectively blocks degradation of cellular proteins that have undergone ubiquitination, such as IkappaB. In fact, proteasome inhibition is a well-established mechanism for blocking NF-kappaB in response to a range of stimuli. A clear advantage to this therapeutic approach is the clinical availability of a systemically administered small molecule bortezomib (Velcadeä), a potent and highly selective boronic acid dipeptide for proteasome inhibition that potentially inhibits chemotherapy-induced activation of NF-kappaB to enhance the apoptotic response to chemotherapy.
To evaluate this therapeutic approach, we determined whether inactivation of proteasome function would inhibit inducible NF-kappaB activation for increased levels of apoptosis in response to chemotherapy and enhanced antitumor effects in vivo. To test our hypothesis, we utilized bortezomib to evaluate the effects of proteasome inhibition on chemotherapy-induced NF-kappaB activation in colorectal cancer cells; apoptosis levels following treatment with chemotherapy; and tumor growth in a xenograft model treated with chemotherapy. Phase I clinical trials to explore how this approach augments chemosensitivity in patients with refractory malignancy were completed. Subsequent work in the laboratory identified a downstream target of NF-kappaB, known as Heparin Binding EGF-like Growth Factor (HB–EGF). We found that selective inhibition of HB–EGF promoted chemotherapy-induced apoptosis in preclinical models of colorectal and pancreatic cancer. We explored the use of a novel inhibitor of HB–EGF in a Phase I/II trial conducted at Mass General and other institutions.
Global Health Research Project: Using CTCs to identify patients at risk for breast cancer in a resource-limited environment (Uganda)
- Mehmet Toner, PhD
- Daniel Haber, PhD, MD, director, Mass General Cancer Center
- James C. Cusack, Jr., MD
- Franklin Huang, MD, PhD
- Elizabeth Sun Mee Biggers, MD
Johanna Riesel, MD
National Institutes of Health (pending)
In cancer patients, circulating tumor cells (CTCs) are a population of tumor-derived cells found in the blood that likely contribute to the establishment of metastatic disease. Detecting CTCs has far-reaching implications for both clinical care and cancer biology. Since these tumor cells are rare, comprising only one in a billion cells in the blood of patients with cancer, it is a tremendous technical challenge for existing cell separation technologies to isolate CTCs. Mehmet Toner, PhD, and Daniel Haber, PhD, MD, have overcome this challenge using a leading-edge, micro-fluidic technology that enables gentle and specific identification of live CTCs in a single step from breast, prostate and lung cancer patients. These isolated CTCs can then be characterized and used to create a non-invasive tool for detecting early disease, monitoring response/resistance to therapy, and culturing viable cells for further study into the growth, resistance and metastatic properties of epithelial cancers. Working with colleagues at the Mbarara University of Science and Technology in Mbarara, Uganda, we plan to evaluate this technology as an early detection tool to diagnose women with breast cancer in a resource-limited setting.
Cost-effectiveness of multidisciplinary management of breast cancer in a resource-limited setting (Rwanda)
- James C. Cusack, Jr., MD
- Robert Riviello, MD, MPH
- Stephen Resch, PhD
- Shilpa Murthy, MD
Global health efforts have tended to focus on managing communicable diseases, such as HIV, Tuberculosis (TB) and childhood infectious illnesses that are preventable with vaccines. Implementation of population-based treatment and prevention programs has successfully reduced the number of fatalities related to communicable diseases that had previously been the two highest contributors (HIV and TB) to death in the developing world. This success has shifted the focus of global health to other high-priority causes of death, including motor vehicle accidents and non-communicable diseases such as cancer.
During a two-week visit in August 2013 to Butaro Hospital and Cancer Center, Rwanda’s national center for cancer care in Burera District, Northern Province, Dr. Cusack was able to train the local surgeon to perform modified radical mastectomies and abdominal perineal resections. His trip was sponsored through a collaboration between the Rwanda Ministry of Health, the Dana-Farber Cancer Institute and the Rwanda Human Resources for Health Program at Harvard Medical School, with the mission of transferring advanced surgical techniques, expanding the health care work force in a comprehensive manner and improving access to advanced health care. This program provides a wide array of opportunities to engage in research projects designed to understand and improve health care delivery in resource-limited settings. Currently, we are working on a project with colleagues at Harvard School of Public Health and Brigham and Women’s Hospital to understand the cost-effectiveness of providing sustainable multidisciplinary management of breast cancer in Rwanda.
Meet our Team
- James C. Cusack, Jr., MD
Research Fellows and Postdoctoral Scholars
- Lukas Liesenfeld, MD (2014-2015)
- Isabel Ferreiro, PhD (2013-2015)
- Carlos Chan, MD, PhD, surgical oncology fellow (2013-2015)
- Nancy Torres, MD (2014-2015)
- Shiwei Han, MD (2015-present)
Medical School Residents
- David Furfuro, HMS4 (2013-present)
- Zhi Fong, MD (2013-present)
- Johanna Riesel, MD (2013-present)
- Shilpa Murthy, MD (2013-present)
Former Lab Fellows
- Michael Houston, third-year medical student, University of North Carolina (UNC)-Chapel Hill (1999-2000)
Award: UNC Medical Scholars Program
Presentations: 32nd UNC Student Research Day, Keystone Symposium (poster); Society of Surgical Oncology (SSO) (oral)
Current: Private practice general surgeon, Concord, NC
- Suzanne Russo, MD, fellow in radiation oncology, UNC-Chapel Hill (1999-2000)
Award: Resident Clinical Basic Science Award
Presentation: American Society for Radiation Oncology (ASTRO)
Current: Associate professor, radiation oncologist, East Carolina University, Greenville, NC
- Robert Esther, MD, PGY2, orthopedic surgery, UNC-Chapel Hill (1999-2000)
Presentation: Musculoskeletal Society Meeting
Current: Assistant professor, Department of Orthopaedics, UNC School of Medicine, Chapel Hill, NC
- Derek Thornton, undergraduate chemistry major, CHEM99, UNC-Chapel Hill (2000-2001)
Presentation: American Cancer Society (ACS) Surgical Forum (oral)
Current: Molecular biology project manager, ILS, Inc., Raleigh-Durham, NC
- Bradley Ellison, MS, second-year medical student, UNC-Chapel Hill (2000-2001)
Award: Holderness Scholarship
Presentation: American Society of Clinical Oncology (ASCO) (poster)
Current: Orthopedics resident, Ohio State University School of Medicine, Columbus, OH
- John Flannery, MD, PGY3, general surgery resident, UNC-Chapel Hill (2001-2003)
Award: ACS Resident Research Fellowship
Current: Private practice, colorectal surgeon
- David Ljungman, MD, postdoctoral fellow, Massachusetts General Hospital (2004-2005)
Current: Colorectal Surgeon, University of Gothenburg, Sweden
- Fang Wang, PhD, postdoctoral fellow, Massachusetts General Hospital (2005-2008)
Presentation: ASCO, 2007 (oral)
Current: Pharmaceutical industry
- Callum Sloss, PhD, postdoctoral fellow, Massachusetts General Hospital (2006-2011)
Current: Pharmaceutical industry
- Juan Antonio Santamaria Barría, MD, postdoctoral fellow, Massachusetts General Hospital (2010-2011)
Presentation: SSO (oral)
Current: Surgery resident, University of Texas at Houston
Research Fellow: Memorial Sloan-Kettering Cancer Center, NY
- Hye-Won Chung, MD, PhD, postdoctoral fellow, Massachusetts General Hospital (2011-2012)
Current: Faculty, South Korea
- Roberto A. Salas Fragomeni, MD, postdoctoral fellow, Massachusetts General Hospital (2011-
Current: General surgery resident, University of Washington