Leader: Matthew D. Ringel, MD
The Molecular Biology and Cancer Genetics (MBCG) research program, one of five trans-disciplinary, highly collaborative research programs at the OSUCCC – James, has a history of high-impact, interdisciplinary and highly collaborative science.
The program includes more than 49 investigators from 19 departments in five of Ohio State University’s 14 colleges. Multiple members have programmatic grants with inter-program collaborations and training grants.
Areas of strength include human cancer genetics, microRNA in cancer, the tumor microenvironment and cell signaling.
Key Program Objectives
- Identify human genes that increase cancer risk through mutation or epigenetic changes
- Identify molecular mechanisms that alter gene expression and function, and influence normal development and cancer progression
- Promote clinical applications of MBCG research to improve cancer diagnosis, prognosis, surveillance, treatment and prevention
MBCG Cancer Focus
- Breast cancer (Ohio ranks 35th among states in breast cancer incidence and fourth for mortality)
- Lung cancer
- Thyroid cancer
- Colorectal cancer
Exposing and Targeting Mechanisms of KRAS Mutant Mediated Radioresistance (RSG-17-221-01-TBG)
PI: Terence Williams, MD, PhD
Objective: Study how mutant KRAS oncogenes induce resistance to radiation therapy, and develop new ways to target resistance mechanisms through molecular, cellular, and cancer cell model approaches.
NCI SPORE: The OSUCCC/MDACC Thyroid Cancer SPORE (P50 CA168505)
Objective: Improve thyroid cancer patient outcomes by:
- Improving predictive testing for aggressive disease
- Improving survivorship, as many patients live for decades after diagnosis
- Improving treatment for aggressive disease
- Improving detection and monitoring of metastases
Genetic Analysis of the Breast Tumor Microenvironment (P01 CA097189)
PI: Michael C. Ostrowski
Objective: Discovering the role of the tumor microenvironment in breast tumorigenesis and translating these discoveries into innovative approaches for the diagnosis and treatment of breast cancer.
Genetic and signaling pathways in epithelial thyroid cancer (P01 CA124570)
PI: Matthew D. Ringel, MD
Objective: Improve the outcomes and lives of patients with thyroid cancer by:
- Identifying genetically "at-risk" individuals, allowing for early diagnosis and prediction of tumor behavior
- Identifying new pathways that influence cancer development and progression
- Improving outcomes of patients with metastatic disease by improving existing therapies or validating new treatment targets
Role of 11q23 chromosome abnormalities in the causation of acute leukemia (P01 CA129242)
PI: Carlo M. Croce, MD
Objectives: ALL1-associated leukemias account for the majority of infant and therapy-related leukemias. This project seeks to further understand how ALL1 fusion proteins trigger leukemia.
MicroRNA profiles of TNBC to define subgroups and targets of therapy (U01 CA154200)
PI: Kaye Huebner, PhD
Objectives: Define the signal pathways that drive important biological features of triple-negative (TN) breast cancers by profiling microRNA expression signatures of TN cancers and associated premalignant lesions. And then, use the miR expression signatures to define signal pathways regulated by miRs that are significantly up- and down-modulated in TN cancers and precursor lesions.
MicroRNAs and UCRs as BMs of cancer risk, early tumor detection, tumor progression and response to treatment (U01 CA152758)
PI: Carlo M. Croce, MD
Objectives: Develop microRNA and ultraconserved non-coding RNA (UCR) biomarkers for the assessment of cancer risk and for the early detection of five different epithelial cancers, including the four most common malignant tumors: lung, breast, prostate and colorectal cancer.
Identifying non-coding RNAs for early detection and prevention of lung cancer (U01 CA166905)
PI: Carlo M. Croce, MD
Objectives: Develop reliable and powerful biomarkers capable to detect malignant disease long before lung cancer is clinically detectable by using a non-invasive approach exploiting microRNA and lncRNA dysregulation in plasma of individuals at risk.
The Ohio Colon Cancer Prevention Initiative (OCCPI), a statewide OSUCCC – James effort that includes __ Ohio hospitals to screen all colorectal cancer patients and their biological relatives for Lynch syndrome (LS), an inherited genetic condition that predisposes to colorectal, endometrial, ovarian and other cancers. LS affects an estimated one of every 370 people in the United States.
Earlier research led by OSUCCC – James researchers determined that an estimated 1 in 35 colorectal cancer patients in Ohio, and 1 in 40 endometrial cancer patients, have Lynch syndrome (LS), an inherited genetic condition that predisposes to colorectal, endometrial, ovarian and other cancers. They further showed that:
- Three additional family members of each affected person have LS
- With about 6,300 colon cancer cases/year in Ohio, about 720 individuals with LS could be identified statewide
- Targeted clinical surveillance can reduce the cancer risk of these family members by 60 percent through increased surveillance.
The OCCPI is led by Heather Hampel, MS, CGC (MBCG); Albert de la Chapelle, MD, PhD (MBCG); Electra Paskett, PhD (CC); Peter Shields, MD (CC).
New mechanism used by cancer cells to disarm attacking immune cells. Immune cells called macrophages are one of the body’s first responders against early cancers. This study found that pancreatic-cancer cells release a factor that disarms attacking macrophages. The findings describe a new mechanism that interferes with immune surveillance and contributes to cancer development.
PI: Denis Guttridge, PhD
Published in the Journal of Clinical Investigation
Characteristic patterns of miRNA in the blood might reveal the presence and aggressiveness of lung cancer. They might also reveal who is at risk of developing the disease. The patterns might be detectable up to two years before the tumor is found by computed tomography. The findings could lead to a blood test for lung cancer.
Senior author: Carlo Croce, MD
Published in the Proceedings of the National Academy of Sciences
Overexpression of the stress gene ATF3 in tumor-associated macrophages might link stress and cancer progression and metastasis. An OSUCCC – James study suggests that cancer cells induce over-expression of ATF3 in tumor-associated macrophages. The study found that high ATF3 in macrophages contributes to progression, suggesting that inhibiting ATF3 in macrophages might inhibit progression.
Senior author: Tsonwin Hai, PhD
Published in the Journal of Clinical Investigation.
Cancer cells alter glutamine metabolism to proliferate under hypoxic conditions in tumors. The study/findings might offer a new strategy for inhibiting tumor growth by reversing this hypoxia-triggered pathway.
PI: Nicholas Denko, MD, PhD
Published in Cell Metabolism
HPV—which causes cervical, head and neck, anal and other cancers—can damage chromosomes and genes where viral DNA inserts into human DNA. The genome-wide analysis identified a striking and recurrent association between HPV integrants and adjacent genomic amplifications, deletions and translocations. The researchers proposed a “looping” model by which abnormal viral replication results in the extraordinary damage that occurs at sites of viral DNA insertion. The results shed new light on the potentially critical, catastrophic steps in the progression from initial viral infection to development of an HPV-associated cancer.
Co-senior authors: David Symer, MD, PhD (MBCG), and Maura Gillison, MD, PhD (CC)
Published in Genome Research
PAK links BRAF to cancer progression. OSUCCC – James researchers identified mechanisms of tumor progression following a clinical observation that PAK is selectively activated in progressive tumors. The researchers confirmed in their large database. In lab cell lines, by molecular inhibiting PAKs they can block invasion and migration; also showed a previously unknown signaling connection between BRAF and PAK. Block BRAF blocks PAK.
PI: Matthew D. Ringel, MD
Published in Endocrine Related Cancer