Translational Research

The Ian C. Summerhayes Cell and Molecular Biology (ICSCMB) Lab at Lahey Hospital & Medical Center performs translational research primarily focused on molecular oncology, and collaborates with high tech corporations pioneering methods of earlier detection of cancer. Additionally, the ICSCMB Lab is actively engaged in an NIH initiative known as TCGA or The Cancer Genome Atlas Project. TCGA is ‘a comprehensive and coordinated effort to accelerate our understanding of the molecular basis of cancer through the application of genome analysis technologies’.

ICSCMB Focus

The ICSCMB lab is focused on the discovery of new genes and cellular pathways implicated in cancer, enhancing understanding of how genetic variations affect the development and progression of cancer. A major focus of the research is to characterize the molecular changes in cancer patients’ tumors by analyzing DNA, RNA and proteins in the tumors and other bodily fluid. The molecular changes can be used as biomarkers for diagnosis, prognosis and prediction of response/resistance to treatment. The lab seeks to facilitate translational application of these findings, first to clinical research in oncology, then to patient care. Of course, the ultimate goal is for physicians to use these markers to select the best treatment with the fewest side effects for each patient.

Urologic Oncology

One of the focuses of our lab is on the molecular basis of genitourinary cancers and improved treatments for patients with prostate, kidney and bladder cancer. Current laboratory research focuses on microRNA (miRNA), a small 22-27 nucleotide RNA species that serves as an mRNA regulator.

Two recent studies have investigated the use of miRNAs as biomarkers for urologic cancer staging. One study identified miRNAs in T1 TURBT specimens that correlate with upstaging at cystectomy. These miRNA have the potential to serve as biomarkers indicative of more aggressive disease. In the second study differential miRNA expression levels were investigated in TRUS biopsies with prostate cancer utilizing a tissue printing method. These samples demonstrated different miRNA expression levels between Gleason Sum (GS) groups (6 vs 7 vs >8). These distinct patterns suggest that certain miRNAs are important at specific stages of prostate cancer progression and holds promise to improve diagnosis, prognosis, and characterization of prostate cancer.

Research: Be a Part of It

Three ongoing studies in the ICSCMB Lab also focus on the utility of miRNAs as biomarkers of cancer staging:

• One study is investigating the potential of miRNAs to identify patients with GS6 prostate biopsies that are upstaged at prostatectomy.
• Another study is screening miRNAs to determine their potential in discriminating bladder cancer patients with occult metastasis.
• A third study is profiling kidney tumors in an effort to identify those individuals who are likely to progress to metastatic disease.

Biospecimen Banking

Biospecimen banking is storing excess human sample that has been removed during a medical procedure such as an operation, a biopsy, or a blood test. This extra material is not needed for your diagnosis or treatment. With your written consent, this material is placed in our biospecimen bank, where it is carefully preserved and protected. We use samples from these banks to study disease and find better ways to diagnose, prevent, and treat cancer in the future.

Rescue Lung/Rescue Life

Lung cancer kills more men and women in the United States than breast, colorectal, and prostate cancers combined with approximately 450 deaths from lung cancer every day. Starting in January 2012, Lahey Hospital & Medical Center began offering free Low Dose CT (LDCT) lung screening to individuals who meet the established high-risk criteria and to date, has evaluated more than 1300 patients.

Biomarkers have the potential to further stratify lung cancer risk in the subgroup of high risk patients, as well as confirming the presence of cancer in patients with suspicious findings. The biomarker-aided diagnosis then could prompt a more aggressive intervention including surgical resection. The current design of the lung screening is based on detecting morphological changes, which usually follow molecular traits with a delay of months to years. Adding biomarker-based testing to the work-up of patients with initial negative scan could increase the accuracy of diagnosis, influence the frequency of follow-up screening visits, improve outcomes, and ultimately reduce costs.

The ISCMB lab is establishing a unique high quality biological sample collection from patients in Lahey’s LDCT screening program. The acquired biosamples will be kept in biorepositories to support current studies on mRNA and miRNA as well as future correlative studies. Combining biomarkers and imaging may allow clinicians to eliminate patients from further diagnostic or therapeutic intervention who are at low risk of disease and to increase intervention for patients who are at increased risk.

Kimberly Rieger-Christ, PhD
Director of Cancer Research

Increasing bacterial resistance to antibiotics is making infections, especially those acquired in medical care settings, harder to treat. Under the direction of George Jacoby, MD, the Lahey Hospital & Medical Center’s Infectious Disease lab has worked on the mechanisms of antibiotic resistance using the tools of bacterial genetics and biochemistry. The hope is that such knowledge will speed treatment of infections with effective antibiotics and facilitate the discovery of new and better antimicrobial agents.

For many years the Infectious Disease lab has worked on β-lactamases, the enzymes that allow bacteria to inactivate penicillins, cephalosporins, carbapenems, and related antibiotics. For the database to which investigators could submit potentially novel β-lactamase sequences for validation and naming (formerly at lahey.org/studies), please visit the National Institute for Biotechnology Information.

Over the past dozen years, this lab has switched to work on bacterial resistance to fluoroquinolones, agents like levofloxacin and ciprofloxacin that kill bacteria by targeting the essential enzymes that twist and untwist DNA as it is replicated and expressed. Mutations in these enzymes can provide quinolone resistance. They discovered that quinolone resistance was also carried by plasmids, small circles of DNA that can be transferred between bacteria, spreading resistance. They purified the responsible protein, named it Qnr, showed that Qnr could protect the target enzymes from quinolone inhibition, and that Qnr protein had a rod-like shape and surface charge mimicking DNA. Qnr genes have been found on plasmids all over the world and also on the chromosome of many bacteria, including samples from the Lahey Microbiology lab. The lab is still studying how Qnr acts, where the qnr gene is found in nature, and what role it played before quinolones were discovered.

George Jacoby, MD
Director

The Tissue Engineering Laboratory integrates engineering principles with biological sciences to advance our knowledge of fundamental cellular processes and accelerate the development of innovative technologies that can have profound and direct applications in patient care. Neuromaterial engineering is a primary focus of our laboratory with the long-term goal of enhancing the quality of life for patients who have sustained traumatic injuries to their peripheral or central nervous system or who suffer from neurodegenerative diseases.

Injuries to the nervous system, whether peripheral or central, result in profound clinical deficits including motor paralysis, lack of protective sensibility and secondary complications such as tissue necrosis and infection. Even with the best technology and current microsurgical techniques available today, less than optimal results are achieved in the treatment of peripheral nerve injury. Understanding and advancing our knowledge of peripheral nerve repair may also ultimately provide clues to improve the management of spinal cord trauma.

The process of nerve regeneration is a complex interplay of cellular elements and molecules which can function both in contact guidance and tropism. Spanning gaps in divided nerves with conduits allow manipulation of this microenvironment. Previous work in in Lahey Hospital & Medical Center’s Tissue Engineering Laboratory demonstrated the enhancement of nerve regeneration with conduits constructed of molecules with piezoelectric properties and have demonstrated the application of electro-spinning technology in nerve regeneration.

Under the direction of Dr. David Bryan, the lab also demonstrated the necessity and role of Schwann cells in the microenvironment of a regenerating growth cone. Migrating from primarily the proximal and to a lesser degree from the distal cut end of the nerve, they provide a physical framework for regenerating growth cone and provide extracellular matrix proteins and specific adhesion molecules facilitating attachment and cell migration. They are also the source of stimulating factors mediated by the release of ligands important in growth and cell signaling. The beneficial effect of one ligand, human recombinant glial growth factor, results in enhanced axonal regeneration and establishment of a functional end point.

Using high- throughput reverse phase protein microarray technology, the Tissue Engineering Laboratory has also identified the spatiotemporal expression of multiple proteins involved in peripheral nerve regeneration. This work allows avenues of inquiry to manipulate the proteins of the nerve microenvironment with the goal of enhancing nerve regeneration.

The current focus of this lab is to investigate the effects of a new class of regulatory molecules, microRNA (miRNA). This family of molecules potentially represents the largest group of regulators in the genome. It is estimated that 60% of genes are regulated by miRNA. miRNA act to down- regulate protein expression through directly binding or degrading the mRNA that codes for a particular protein. They arise from introns of DNA as it is spiced in the nucleus. This class of molecules has potential clinical applications and synthetically produced mimics of some miRNA are currently being used in clinical trials.

David. J. Bryan, M.D., FACS
Director

Lahey Hospital & Medical Center’s Laboratory of Tissue Regeneration focuses on the most significant problems in reconstructive surgery, motivated by many of our cancer and trauma patients. Whether developing new strategies to treat serious wounds, coming up with innovative ways of connecting small blood vessels or studying methods to re-grow nervous tissue, the Laboratory of Tissue Regeneration staff is dedicated to improving patient outcomes. These efforts provide the foundation for further advancement in healing technologies, targeting patients with major reconstructive needs.

As one of the leading laboratories in wound healing research, the Laboratory of Tissue Regeneration uses a unique mouse model to study the various aspects of the wound healing process, finding new and better ways to improve the quality and time of healing. With the growth of complicated surgeries, wound healing research is an essential aspect of reconstructive surgery.

The laboratory is also working towards improving the efficiency, safety and reliability of microvascular anastomosis: a technically demanding and time consuming surgery to reconnect the blood vessels to allow transfer of tissues for coverage of large defects. The goal of Lahey’s Laboratory of Tissue Regeneration is to benefit cancer, trauma and transplant patients by making such free tissue transfer a routine surgery.

In addition, the lab is working in collaboration with another lab to develop a new method of gene transfer in neuronal tissue that they expect will enhance peripheral nerve regeneration. Advancements in this research will help patients regain function and sensation in their bodies after major cancer and trauma procedures.

Lifei Guo, MD, PhD, FACS
Director