Profiles in Cancer Research
New Compound Shows Potential for Triple-Negative Breast Cancer
An investigation from the University of Michigan could eventually lead to new therapies that take aim at the most aggressive type of breast cancer.
Here is the link to an exciting breakthrough in cancer research:
Some Breast Cancer Patients Missing Out on Genetic Counseling
A new study finds only half of women who could benefit from genetic testing get it, and often not before they have surgery.
Here is the link to this article:
“I’ve devoted my scientific career to understanding the reasons why tumors become very aggressive and
Sofia Merajver, M.D., Ph.D.
Scientific Director, Breast Cancer Program
Director, Breast and Ovarian Cancer Risk Evaluation Program
Professor of Internal Medicine and Epidemiology
Cures and prevention for aggressive breast and ovarian cancers
Research in the Merajver Lab
Over the last 40 years, scientists have made significant strides in understanding, diagnosing, and treating breast cancer. Today, when breast cancer is detected and treated early, a woman’s change of surviving is greater than 70 percent — a rate that has doubled since the 1970s. However, breast and ovarian cancers are still killing thousands of women everywhere. And, it’s the cancers that come back that cause the majority of these deaths.
Under the leadership of Dr. Sofia Merajver, the University of Michigan Comprehensive Cancer Center is committed to conquering especially aggressive breast and ovarian cancers, and to helping patients survive and live well.
In our quest to uncover cures, several critical questions remain unanswered:
• How do breast and ovarian cancers develop in women at increased risk, such as BRCA carriers?
• When cancers are diagnosed while tumors are still small, how can we know whether they harbor cells that are capable of spreading to other organs?
• How and why does
This new understanding demands a personalized approach, also known as precision medicine: delivering the right therapy to the right patient at the right time. As an institution, we’ve prioritized precision medicine, and the Merajver lab is collaborating across many disciplines to bring scientific advances to every patient in real time.
The team is focused on integrating cell biology, genetics, and drug development, as they come together to corner and defeat cancer. And, since Dr.
Specifically, with help from philanthropic support, we are pursuing the following projects:
Eliminating cells that are capable of spreading in aggressive cancers
Many women who expect that they are cured after their initial treatments, experience the spread of their cancer a few short years hence. Dr.
In that effort, Dr.
Developing new drugs for inflammatory breast cancer
The Merajver lab was the first to discover that the gene RhoC is consistently overexpressed in inflammatory breast cancer tumors. It turns out that
Further, based on the critical role of
Addressing inflammation in breast and ovarian cancer
We are now determining which specific substances put out by the macrophages affect the potential of cancer cells to spread.
Managing hereditary breast and ovarian cancer
As the director of the Breast and Ovarian Risk Evaluation Clinic, Dr.
We are currently planning a prevention clinical trial using
YOU CAN BE A VICTOR
We’re especially proud of our partnership and deep ties with breast cancer advocates, survivors, patients, volunteers and generous supporters, who’ve made a significant contribution to cancer discovery, training tomorrow’s leaders, and ultimately, to saving lives.
As we stand at the brink of phenomenal advances, greater investments in breast and ovarian cancer research are needed now to harness the full potential of the U-M and accelerate the Merajver lab’s progress at this critical juncture in cancer science.
Dr. Carrie R. Graveel
Senior Research Scientist
Van Andel Research Institute
Dr. Carrie R. Graveel earned her Ph.D. in Cellular and Molecular Biology from the University of Wisconsin-Madison in 2002. She then served as a postdoctoral fellow in the laboratory of Dr. George Vande Woude at Van Andel Research Institute (VARI) from 2002-2007. In 2007, Dr. Graveel became a Research Scientist and in 2010 was promoted to Senior Research Scientist and is currently working with Dr. Matthew Steensma (Van Andel Research Institute, Spectrum Health). In 2011, Dr. Graveel became an Instructor in the VAI Graduate School. Dr. Graveel’s work was the first to determine that a mutationally activated receptor tyrosine kinase (MET) can induce diverse tumors in in vivo models. In 2009, Dr. Graveel was the first to demonstrate that MET plays a critical role in triple-negative breast cancer and may be an attractive target for clinical treatment. Recently, Dr. Graveel demonstrated that MET may play a role in therapeutic resistance of HER2+ and triple-negative breast cancers. Currently, her work focuses on how kinase signaling networks drive tumor progression and can be leveraged to develop effective therapeutic strategies for breast cancer.
Targeting MET and EGFR in Triple-Negative Breast Cancer
Receptor tyrosine kinase signaling can promote the growth, invasion, and survival of both normal and cancerous cells. In cancer, altered receptor tyrosine kinase signaling is frequently exploited to drive tumor initiation, progression and metastasis. Understanding how these receptors signal in breast cancer cells is critical to our development of successful therapeutic strategies. Our laboratory is working to identify novel therapeutic targets and prognostic signatures of therapeutic resistance in breast cancer.
Triple-negative breast cancer (TNBC) accounts for 15-20% of breast cancers and is associated with advanced stage at diagnosis and poorer outcome compared to other breast cancer subtypes. Treatment options for TNBC patients are restricted to chemotherapy; however tyrosine kinases are promising druggable targets due to their high expression in TNBC. The success of Herceptin in HER2+ breast cancer underscores the promise of targeting tyrosine kinases. In spite of this promising start, acquired resistance is a significant clinical issue for kinase inhibitors, in part due to compensation signaling through other kinases. Recent clinical studies in non-small cell lung cancer (NSCLC) suggest that combinatorial MET and EGFR inhibition improves and prolongs therapeutic efficacy in a subset of patients. While MET and EGFR are expressed in the majority of TNBCs, we have evidence that TNBC has de novo resistance to EGFR inhibition through MET activation and that MET and EGFR inhibition is effective in abrogating TNBC tumor progression. For clinical success to become a reality with kinase inhibitors, it is imperative that we understand the compensatory mechanisms by which tumors develop resistance. The goal of our research is:
To determine the MET and EGFR expression, activation, and signaling interactions in triple-negative breast cancer.
To determine the common downstream signaling pathways of MET and EGFR that drive breast cancer progression and resistance.
To determine the efficacy of MET and EGFR inhibition on triple-negative breast cancer progression in vivo.
Our studies combine a novel aggregate of innovative proteomic and genomic approaches and in vivo models of TNBC. With these methods, we are investigating the unique molecular drivers of TNBC and will gain a significant understanding of the role of MET, EGFR, and additional signaling pathways in TNBC. These studies will identify how MET and EGFR promote therapeutic resistance and identify effective treatment combinations for TNBC patients.
NF1 is a critical tumor suppressor and potential driver of breast cancer
Neurofibromatosis type 1 (NF1) is a tumor predisposition syndrome that is caused by germline mutations in the NF1 gene and is the most common single-gene disorder affecting 1 in 3,000 live births. The NF1 gene encodes for the protein neurofibromin which negatively regulates RAS. Deregulated RAS is a critical driver of numerous cancers. The majority of patients with NF1 develop benign cutaneous neurofibromas and may also develop peripheral nerve tumors, neurocognitive disorders, and bone stigmata (tibial dysplasia, scoliosis, and osteoporosis). Importantly, NF1 patients also have an increased risk of developing several adult cancers including breast, ovarian, liver, lung, bone, thyroid, and gastrointestinal cancers. More recently, NF1 has been implicated in a significantly increased breast cancer risk. A study in England observed that women with NF1 have an increased relative risk of developing breast cancer particularly in their younger years.
In addition to inherited mutations, NF1 mutations and deletions commonly occur in sporadic cancers. For example NF1 is the third most prevalent mutated or deleted gene in glioblastoma, fourth most mutated gene in ovarian cancer, and the second most common mutated tumor suppressor in lung adenocarcinoma. Comprehensive genomic analyses have also revealed that NF1 is commonly mutated in sporadic breast cancers and may be an important driver in sporadic breast cancer. Our lab is investigating how NF1 deficiency promotes both inherited and sporadic breast cancer. By analyzing genomic datasets, we have determined that 25% of breast cancer patients have genomic NF1 deletions. Moreover, patents with NF1 deletions are 1.65X more likely to die within the first 10 years after diagnosis. To examine the effect of functional NF1 loss on tumorigenesis, we created an in vivo model of NF1 deficiency using a CRISPR-Cas9 gene editing strategy. This novel NF1 model develops highly penetrant, and aggressive mammary adenocarcinomas. To our knowledge, this is the first model of NF1‑related breast cancer. Currently, we are investigating the role of NF1 and deregulated RAS signaling in breast cancer initiation and the efficacy of RAS pathway inhibitors in NF1‑related breast cancers.