Ovarian, Glioblastoma & Non-Small Cell Lung Cancer: Jefferson Researchers Present at AACR

Several researchers from Jefferson’s Kimmel Cancer Center presented abstracts at the American Association for Cancer Research Annual Meeting 2012 in Chicago. Some of those findings include:

HuR and Ovarian Cancer

Silencing HuR may be a promising therapeutic approach for the treatment of ovarian cancer, according to an abstract presented at AACR by researchers from Thomas Jefferson University, Lankenau Institute for Medical Research, the Geisinger Clinic and the Massachusetts Institute of Technology.

HuR is a RNA-binding protein that post-transcriptionally regulates genes involved in the normal cellular response to cancer-associated stressors, like DNA damage, nutrient depletion and therapeutic agents.  When triggered by stress, HuR translocates from the nucleus to the cytoplasm where it potently influences translation of key tumor promoting mRNAs by mRNA stabilization and direct facilitation of translation.

Previously, it has been shown that HuR expression is a prognostic marker in ovarian cancers. Thus, researchers tested the effects of manipulating HuR expression levels on ovarian tumor growth characteristics and tested the hypothesis that silencing HuR through delivery of an HuR siRNA would be effective in suppressing the growth of ovarian tumors.

Following treatment of ovarian cancer cells in culture with an adenovirus containing the HuR coding sequence, HuR expression was increased by about 40% above control cells.

In the patient cohort, researchers also detected HuR activation (i.e., cytoplasmic HuR positivity) in twenty-four of thirty four patients (71 percent), providing evidence that the majority of patients have activated HuR.

“These data provide evidence that silencing HuR, even as a monotherapeutic strategy, may be a promising therapeutic approach for the treatment of ovarian cancer,” wrote the authors.

Authors of the paper include Janet A. Sawicki and Yu-Hung Huang, of Lankenau Institute for Medical Research, Charles J. Yeo, Agnieszka K. Witkiewicz, Jonathan R. Brody, of Thomas Jefferson University, Radhika P. Gogoi, of Geisinger Clinic, Danville, Pa., and Kevin Love and Daniel G. Anderson, of Massachusetts Institute of Technology, Cambridge, Mass.

This work was supported by the Marsha Rivkin Center for Ovarian Cancer Research.

Radiotherapy and Glioblastoma

Radiotherapy’s effect on glioblastoma (GBM) is enhanced in the presence of a heat shock protein and a P13K inhibitor, researchers from the Department of Radiation Oncology reported at AACR.

Glioblastoma tumors frequently contain mutations in the tumor suppressor gene, PTEN, leading to loss of PTEN activity, which causes overactivation of the PI3K pathway, inducing inhibition of apoptosis and radioresistance.

Heat-shock protein 90 (HSP90) is a molecular chaperone that is over-expressed in GBM and that has among its client proteins, PI3K and Akt.

It was hypothesized that dual inhibition of HSP90 and PI3K signaling would additively or synergistically radiosensitize GBM through inhibition of radiation-induced PI3K/Akt signaling, leading to enhanced apoptosis.

Confirming their theory, the researchers found that the response of glioblastoma to radiotherapy was enhanced in the presence of BKM120 and HSP990. Enhanced apoptosis also contributed to the mechanism of cell death.

Authors of the study include Phyllis Rachelle Wachsberger, Yi Liu, Barbara Andersen, and Adam P. Dicker, of the Department of Radiation Oncology at Thomas Jefferson University Hospital and Richard Y. Lawrence, of Jefferson and the Sheba Medical Center, Tel Hashomer, Israel.

This work was supported by a grant from Novartis Pharmaceuticals.

Non-Small Lung Cancer and DACH1

Researchers from the Kimmel Cancer Center at Jefferson have identified a protein relationship that may be an ideal treatment target for non-small cell lung cancer (NSCLC).  They presented their findings at AACR.

DACH1, a cell fate determination factor protein, appears to be a binding partner to p53, a known tumor suppressor, which inhibits NSCLC cellular proliferation.

As cancer develops and becomes more invasive, the expression of DACH1 decreases. Clinical studies have demonstrated a reduced expression of the DACH1 in breast, prostate and endometrial cancer.

In a previous study of more than 2,000 breast cancer patients, Jefferson researchers found that a lack of DACH1 expression was associated with a poor prognosis in breast cancer patients. Patients who did express DACH1 lived an average of 40 months longer.

Genetic studies have identified several oncogenes activated in lung cancer, including K-Ras and EGFR. Given the importance of the EGFR in human lung cancer, researchers examined the role of DACH1 in lung cancer cellular growth, migration and DNA damage response.

For this study, endogenous DACH1 was reduced in human NSCLC, with expression levels of DACH1 correlating inversely with clinical stage and pathological grade.

Re-expression of DACH1 also  reduced lung cancer cell colony formation and cellular migration. Cell cycle analyses demonstrated that G2/M block by ectopic expression of DACH1 occurs synergistically with p53.

Fluorescent microscopy demonstrated co-localization of DACH1 with p53, and immunoprecipitation and western blot assay showed DACH1 association with p53.

“DACH1 enhanced the cytotoxcity of cisplatin and doxorubicin, two commonly used drugs for NSCLC,” the authors write in the abstract. “Together, our studies demonstrate that p53 is a DACH1 binding partner that inhibits NSCLC cellular proliferation.”

Authors of the study include Ke Chen, Kongming Wu, Wei Zhang, Jie Zhou, Timothy Stanek, Zhiping Li, Chenguang Wang, L. Andrew Shirley, Hallgeir Rui, Steven McMahon, Richard G. Pestell, of  Thomas Jefferson University, Kimmel Cancer Center and Huazhong University of Science and Technology, Wuhan, China.



PCF Young Investigator Award Goes to Jefferson Researcher

Heather Montie, Ph.D., a post-doctoral research fellow in the Department of Biochemistry and Molecular Biology, has received a Prostate Cancer Foundation Young Investigator Award for her work with androgen receptor (AR) acetylation and its role in castration-resistant prostate cancer.

Young Investigator awards are designed to promote long-term careers in the field of prostate cancer by providing three year grants for transformational research focused on prostate cancer treatments to improve patient outcomes. Since 2007, PCF has invested more than $20 million in Young Investigator grants.

“PCF-supported young investigators have changed the scope of prostate cancer research, advancing treatment sciences and improving the lives of patients worldwide,” said Howard Soule, PhD, chief science officer and executive vice president of PCF. “It is with great pride and appreciation that PCF can now announce our young investigator program spans across six countries and 42 research institutes.”

Prostate cancer is driven by the male hormones, androgens which mediate their activity through the androgen receptor. Unfortunately most prostate cancerous tumors progressively become resistant to the preferred treatment modality, androgen deprivation therapy. One of the mechanisms proposed to enhance the activity of androgen receptors in castration-resistant prostate cancer, even in the absence of androgens, is the addition of a small chemical group/moiety to the AR protein. This modification of AR is termed ‘acetylation’ and is proposed to convert the protein to a ‘super AR.’

However, there is currently no experimental data to show that AR acetylation directly enhances AR-dependent prostate cancer cell viability.

Dr. Montie proposes to evaluate the role of AR acetylation in the enhanced AR functional activity central to CRPC. She will study the precise mechanisms by which this modification of AR enhances its cancer-promoting activity. Dr. Montie will also validate the potential of AR acetylation as a therapeutic target for castrate-resistant prostate cancer.

A total of 15 competitive research grants have been awarded to-date in 2012, bringing the total of young investigators awarded to 89.

Each Young Investigator recipient is awarded $225,000 over a three-year period.

Dr. Montie received the 2012 John A. Moran PCF Young Investigator Award. 

Visit here for more on the Young Investigator awards.



Drugs targeting chromosomal instability may fight a particular breast cancer subtype

Richard Pestell, M.D., Ph.D, Director of the KCC

Another layer in breast cancer genetics has been peeled back.

A team of researchers at Jefferson’s Kimmel Cancer Center (KCC) led by Richard G. Pestell, M.D., PhD., FACP, Director of the KCC and Chair of the Department of Cancer Biology, have shown in a study published online Feb. 6 in the Journal of Clinical Investigation that the oncogene cyclin D1 may promote a genetic breakdown known as chromosomal instability (CIN). CIN is a known, yet poorly understood culprit in tumor progression.

The researchers used various in vitro and in vivo model systems to show that elevated levels of cyclin D1 promotes CIN and correlate with CIN in the luminal B breast cancer subtype. Cyclin D1 protein is elevated in breast, prostate, lung and gastrointestinal malignancies.

The findings suggest that shifting towards drugs targeting CIN may improve outcomes for patients diagnosed with luminal B subtype. Luminal B breast cancer has high proliferation rates and is considered a high grade malignancy.

Estrogen or progesterone receptor positive and HER2 positive cancers indicate luminal B, and about 10 percent of patients are diagnosed with it every year, though many do not respond well to treatment. The identification of CIN in luminal B provides a new therapeutic opportunity for these patients.

“Cyclin D1 has a well defined role in cell proliferation through promoting DNA replication,” says Dr. Pestell. “My team was the first to discover that cyclin D1 also has alternate functions, which include regulating gene transcription at the level of DNA. We were interested in discovering the function of DNA associated cyclin D1.”

To help answer this, the researchers, including lead author Mathew C. Casimiro, Ph.D., of the Department of Cancer Biology at Thomas Jefferson University, first needed to directly access cyclin D1′s role in gene regulation.

They applied an analysis known as ChIP sequencing to study the protein’s interactions with genes that comprise the entire mouse genome, and found it occupied the regulatory region of genes governing chromosomal stability with high incidence.

They went on to show cyclin D1 promoted aneuploidy and chromosomal rearrangements typically found in cancers.

Faulty chromosomes—either too many or too few, or even ones that are the wrong shape or size—have been shown to be the crux of many cancers. However, a major question of cancer genetics is the mechanisms of CIN. What causes the breakdown in chromosomal stability?

As cyclin D1 expression is increased in the early phases of tumorigenesis, cyclin D1 may be an important inducer of CIN in tumors.

To analyze the association between CIN and cyclin D1 expression in the context of breast cancer, the team aligned an expression of a 70-gene set with the highest CIN score against over 2,000 breast cancer samples. They stratified the samples based on previously described subtypes and aligned them with cyclin D1 expression profiled across the dataset.

A significant correlation among CIN, cyclin D1 and the luminal B subtype was identified, and it was apparent that the relationship between these levels was subtype specific.

“Interestingly, previous studies have presented contradictory results,” Dr. Pestell says. “Many studies have suggested a positive correlation between cyclin D1 expression and outcomes, while others have shown reduced survival. Here, we’ve dug deep, using a genome-wide analysis, and found that overexpression of the protein appears to be directly associated with the genes involved in CIN and this correlates with the luminal B subtype.”

Drugs targeting chromosomal instability for cancer therapy have been explored, but a sub-stratification rationale for the luminal B subtype has not been established. The research presented in this study suggests such a target is worthy of further investigation.

“There is a big drive towards using targeting therapies for stratified breast cancers,” says Dr. Casimiro. “What we are thinking is that there are a growing number of drugs that target aneuploidy, like AICAR and 17-AAG, that may be used as an adjuvant therapy in patients with luminal B breast cancer.”



Loss of RB in Triple Negative Breast Cancer Associated with Favorable Clinical Outcome

Researchers at the Thomas Jefferson University Hospital and Kimmel Cancer Center at Jefferson have shown that loss of the retinoblastoma tumor suppressor gene (RB) in triple negative breast cancer patients is associated with better clinical outcomes. This is a new marker to identify the subset of these patients who may respond positively to chemotherapy.

Today, no such marker is applied in care of triple negative breast cancer, and as a result, patients are all treated the same.

Agnieszka Witkiewicz, M.D., Associate Professor of Pathology, Anatomy and Cell Biology at Thomas Jefferson University, and Erik Knudsen, Ph.D., Professor of Cancer Biology and Deputy Director of Basic Science at Jefferson’s Kimmel Cancer Center, presented the findings at the 2011 CTRC-AACR San Antonio Breast Cancer Symposium during a poster discussion on Dec. 9.

“This is a step in trying to better direct treatment for patients with triple negative breast cancer,” Dr. Knudsen said.

In general for cancer, loss of tumor suppressor genes is associated with poor clinical outcome. However, loss of RB in triple negative breast cancer patients appears to be a predictor of favorable clinical outcomes.  This is because it changes the way tumor cells respond to therapy such that they end up becoming more sensitive to chemotherapy.

The researchers retrospectively evaluated the RB status and clinical outcome of a cohort of 220 patients diagnosed and treated at Thomas Jefferson University Hospital with chemotherapy.  RB loss, they found, was associated with a longer overall survival. In contrast, patients with RB had worse survival.

“Triple negative breast cancer is the most deadly of breast cancers, with fast-growing tumors, that affects younger women,” said Dr. Witkiewicz. “This work allowed us to identify a marker that could lead to better treatment for patients. It’s about female personalized medicine.”

Edith Mitchell, M.D., Professor of Medical Oncology at Jefferson, and Adam Ertel, Ph.D., a research instructor in the Department of Cancer Biology, were also involved in the study.

The next step for the researchers is a clinical trial at Jefferson to confirm their findings. Tumors of newly-diagnosed patients with triple negative breast cancer will be tested for the RB gene before they receive chemotherapy. After treatment, the data will be evaluated to determine the efficacy of directing future patient care.

This study represents one important example of personalized medicine being performed at the Department of Pathology, Anatomy and Cell Biology, Thomas Jefferson University and the Kimmel Cancer Center to improve patient care.



Jefferson Researchers Unlock Key to Personalized Cancer Medicine Using Tumor Metabolism

Identifying gene mutations in cancer patients to predict clinical outcome has been the cornerstone of cancer research for nearly three decades, but now researchers at the Kimmel Cancer Center at Jefferson have invented a new approach that instead links cancer cell metabolism with poor clinical outcome. This approach can now be applied to virtually any type of human cancer cell.

Michael P. Lisanti, M.D., Ph.D., Professor and Chair of Stem Cell Biology & Regenerative Medicine at Jefferson Medical College of Thomas Jefferson University, Kimmel Cancer Center at Jefferson

The researchers demonstrate that recurrence, metastasis, and poor clinical outcome in breast cancer patients can be identified by simply gene profiling cancer cells that are using ketones and lactate as a food supply.

These findings are reported in the April 15th online issue of Cell Cycle. The investigators are calling this new approach to personalized cancer medicine “Metabolo-Genomics.”

High-energy metabolites have long been suspected to “fuel” aggressive tumor cell behavior. The researchers used this premise to generate a gene expression signature from genetically identical cancer cells, but one cell group was fed a diet of high-energy metabolites. These lactate- and ketone-induced “gene signatures” then predicted recurrence, metastasis, and poor survival.

So, it appears that what cancer cells are eating determines clinical outcome, not necessarily new gene mutations.

Michael P. Lisanti, M.D., Ph.D., Professor and Chair of Stem Cell Biology & Regenerative Medicine at Jefferson Medical College of Thomas Jefferson University and a member of the Kimmel Cancer Center at Jefferson, together with other researchers,  found that treatment of human breast cancer cells with high-energy metabolites increases the expression of genes associated with normal stem cells,  including genes upregulated in embryonic and neural stem cells.

What’s more, lactate and ketones were found to promote the growth of normal stem cells, which has critical applications for stem cell transplantation and for a host of different human diseases.  It appears that these metabolites increase “stemness” in cancer cells, which drives poorer outcomes.

“Tumors that are using the body’s own nutrients (lactate and ketones) as “fuel” have a poorer outcome for patient survival, a behavior that now can be used to predict if a patient is at a high-risk for recurrence or metastasis,” Dr. Lisanti said. “This is getting to the heart of personalized cancer medicine. Now, we have identified a panel of biomarkers that directly links cancer metabolism with targeted cancer therapy.”

These findings suggest, according to the authors, that high-risk cancer patients (those whose cancer cells use high-energy metabolites) can be treated with new therapeutics that target oxidative mitochondrial metabolism, such as the antioxidant metformin, a drug that is also used to treat diabetes.

“Knowing the gene signatures of patients whose cancer cells are “eating” these metabolites for fuel is a pivotal piece of new information that we can use to diagnose and treat cancer patients,” said Martinez-Outschoorn, M.D., of the department of Medical Oncology at Thomas Jefferson University, and the lead author of the paper. “It’s not just that we know those patients will have poor survival; we know that those patients are using mitochondrial metabolism, which is the type of energy metabolism that we should be targeting with new anti-cancer drugs.”

The researchers propose that this new approach to diagnosis and subsequent treatment be called “Metabolo-Genomics” since it incorporates both cell metabolism and gene transcriptional profiling. This strategy could now be used to direct which patients receive a particular “tailored” anti-metabolic therapy.

Genetic markers, like expression of the mutationally activated HER2 gene, provide biomarkers that can be used to identify breast cancer patients at high-risk for recurrence or metastasis, and to modify their subsequent treatment with targeted therapies (i.e., herceptin, a drug used in aggressive breast cancers).  But with “Metabolo-Genomics,” it is now about using “global” cancer cell metabolism for these predictions.

“Just by feeding cancer cells a particular energy-rich diet, it changes their character, without introducing mutations or altering their genetic profile,” Dr. Lisanti said.  “We’ve only fed them high energy nutrients that help them to use their mitochondria, and this changes their transcriptional profile.  It’s a new biomarker for “lethal” cancers that we can now treat with the right drugs, such as the antioxidant metformin.

Dr. Lisanti and his colleagues believe that tumor metabolism is the new big picture for understanding how cancers undergo recurrence and metastasis.



“How & Why” Cancer Cells Eat Us Alive

Four key studies now propose a new theory about how cancer cells grow and survive, allowing researchers to design better diagnostics and therapies to target high-risk cancer patients.  These studies were conducted by a large team of researchers at Thomas Jefferson University’s Kimmel Cancer Center.
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