Stephen Lyle, M.D., Ph.D.
Associate Professor and Director,
UMass Cancer Center Tissue Bank
Dept's. of Cancer Biology and Pathology
UMass Medical School

Over the past several years, doctors and cancer scientists have realized that tumors, similar to normal tissues, are made up of a mixture of cells. Thus, a patient does not just have one type of cancer cell but many different cancer cells that may behave differently. Some cells within the tumor are cured easily by chemotherapy and radiation while other cancer cells may survive, only to re-grow or spread to other organs; and this represents a major challenge to effectively treating cancer patients. Recently, we have recognized that colon cancers contain small numbers of “cancer stem cells” that may be especially resistant to chemotherapy and radiation treatments and thus may be responsible for recurrence of the tumor after therapy. The research laboratory of Dr. Stephen Lyle is studying rare cancer stem cells within colon cancers so that we can better eliminate these cells and kill cancer at its root.

Work in the laboratory of Stephen Lyle focuses on stem cells and cancer, including colorectal cancer. There are three important reasons to think about adult stem cells and cancer.

• Normal adult stem cells possess the self-renewal properties of cancer cells and thus can serve as a model system for study.
• Stem cells may be targets of carcinogenic pathways. Since adult stem cells reside in the body for your life-time, they can accumulate multiple genetic mutations which lead to cancer. Can we protect our stem cells and prevent cancer?
• Do cancers, as abnormal tissues, contain a subpopulation of cells with stem cell qualities; “cancer stem cells”? If so, what are their properties and how can this be exploited therapeutically?

We are developing ways to identify and target “cancer stem cells” in colon cancer.

Publications:

• Grossman SR, Lyle S, Resnick MB, Sabo E, Lis R, Rosinha E, Liu Q, Hsieh C-C, Bhat G, Frackleton AR, Hafer LJ. P66 Shc tumor levels show a strong prognostic correlation with disease outcome in stage II colon cancer. Clin. Can. Res. 2007, Oct 1;13(19): 5798-804.
• Li H, Fan X, Stoicov C, Liu JH, Zubair S, Tsai E, Ste Marie R, Wang TC, Lyle S, Kurt-Jones E, Houghton J. Human and mouse colon cancer utilizes CD95 signaling for local growth and metastatic spread to liver. Gastroenterology. 2009 Sep;137(3):934-44

Collaborative work between the labs of Drs. Stephen Lyle and JeanMarie Houghton was profiled on the cover of the journal “Gastroenterology.”

Steven R. Grossman, MD, PhD
Associate Professor of Cancer Biology and Medicine
Co-Director, GI Cancer Program
UMass Medical School/UMass Memorial Cancer Center

Our laboratory focuses on the function of proteins in cells that normally prevent cancers, such as colorectal cancer. These powerful cancer fighting proteins include p53 and p14ARF. Most colon cancers demonstrate the loss by mutation or lack of expression of one of these tumor suppressors. Our goal is to understand how these proteins fight cancer at the cell level, in order to design therapies that could restore their function in cancers where they have been inactivated-specifically targeting treatments to the types of distinct changes that occur in an individual cancer patient. Our first therapeutic drug candidate arising from this work is currently being tested in a mouse model of colon cancer. This therapeutic candidate targets an enzyme –CtBP- that is normally inactivated by p14ARF, and our research predicts might be hyperactivated (overexpressed) in colon cancer tumors that have lost ARF.

Publications:

1. Kovi RC, Paliwal S, Pande S, Grossman SR. An ARF/CtBP2 complex regulates BH3-only gene expression and p53-independent apoptosis. Cell Death Diff 2009; Oct 2, Epub ahead of print.
2. Paliwal S, Kovi RC, Nath B, Chen YW, Lewis BC, Grossman SR. The Alternative Reading Frame Tumor Suppressor Antagonizes Hypoxia-Induced Cancer Cell Migration via Interaction with the COOH-Terminal Binding Protein Corepressor. Cancer Res. 2007; 67:9322-9329.
3. Grossman SR*, Lyle S, Resnick MB, Sabo E, Lis RT, Rosinha E, Liu Q, Hsieh CC, Bhat G, Frackelton AR Jr, Hafer LJ. p66 Shc Tumor Levels Show a Strong Prognostic Correlation with Disease Outcome in Stage IIA Colon Cancer. Clin Cancer Res 2007; 13:5798-5804. [*corresponding author]
4. Paliwal S, Pande S, Kovi R, Sharpless NE, Bardeesy N, Grossman SR. Targeting of C-terminal Binding Protein (CtBP) by ARF results in p53-independent apoptosis. Mol Cell Biol 2006; 26:2360-2372.

COLORECTAL SURGERY DIVISION

Justin Maykel MD, Karim Alavi MD, Brian Sweeney MD, Paul Sturrock MD, Janet McDade NP, Andres Cervera MD

1. Anal Cancer Database.
   • Previous records review of all patients with anal cancer (Retrospective Collection of data)
   • Prospectively reviewed and maintained.
   • Evaluation of trends, predictive factors as well as treatment response and follow up of patients treated in UMass.
   • Outcomes Comparison with national standards.
   • Adequate follow up and evaluation of these results will provide a better understanding of this disease’s behavior and clinical response. Further research and treatment options will be evaluated and developed using this database.
2. Colon and Rectal Database - Under development.
3. Translational Research
   • Foster collaborative research, seeking clinical application of newly developed technology in the Colorectal Cancer area.
   • Evaluation of injection of a substance developed at UMass intratumorally in patients with recurrent or persistent Anal Cancer.
4. Evaluate Impact of Diversity on the Treatment of Colon and Rectal Cancer Patients
   • Patients with diverse characteristics (ethnicity, gender, religion, insurance status, socioeconomic status) receive equal care by the UMASS Colorectal Surgery Service.
   • To evaluate and ensure that patients with colorectal cancer at UMass are receiving the same quality of care regardless of their ethnicity, gender, religion, socioeconomic or insurance status).
5. Retrospective study to evaluate the utility of repeat CT scan in Restaging of Rectal Cancer after neoadjuvant chemotherapy and radiation.
   • Restaging CT Scan after neoadjuvant therapy for Rectal Cancer is routinely used in UMass.
   • With this retrospective study we seek to evaluate the usefulness and overall impact on decision making of this CT, as well as the clinical scenarios where it is necessary.
   • Pending results, a significant reduction in cost could be demonstrated in the management of Rectal Cancer patients.
6. UMass Employee Colorectal Cancer Screening Program
   • For promoting awareness, removing financial and time-off barriers, generating a healthy competition will result in increased rates of colorectal cancer screening.
   • Launched March 2009 100 employees screened
     • **1 colon cancer identified in an asymptomatic patient
7. Outpatient Colectomy
   • A select group of patients can safely recover at home starting the first day following colon resection.
   • Prospective study to evaluate and demonstrate the feasibility of performing colon resections in an outpatient basis.
   • If demonstrated this will allow to decrease the cost of Cancer treatment, and allow patients to recover in a faster more comfortable setting at Home.
8. Incorporation of Simulation into Colorectal Surgery Curriculum for Medical Students and Residents
   • Thorough understanding and simulation practice in detecting clinical and endoscopic findings related to Colorectal Cancer will provide undergraduate Medical students and postgraduate Residents with a higher capability of Early Detection of Cancer with increased patient safety.
9. Influence of coffee in prevention of post-operative ileus
   • IRB approved, soon to be launched study to evaluate coffee as a promoter of bowel activity after colon surgery. Pending Grant.
   • Decrease in rate of postoperative ileus will allow faster recovery, shorter length of stay in hospitals and decrease overall cost in Colorectal cancer patients