Potential Combination Therapy For Esophageal Cancer?

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Researchers have identified a non-traditional pathway for stimulating a cancer-promoting protein into the cell nucleus that could be a potential combination therapy for esophageal cancer. The finding suggests a resistance mechanism for new drugs that attack the Hedgehog pathway.

In the March 20 issue of the journal Cancer Cell, researchers at The University of Texas MD Anderson Cancer Center reveal that the mTOR molecular pathway stimulates the activity of the Gli1 protein in the development and progression of esophageal cancer.

Senior author of the study, Mien-Chie Hung, Ph.D., vice president for basic research, professor and chair of MD Anderson's Department of Molecular and Cellular Oncology, explained: "The Hedgehog pathway is the established, or canonical, pathway for activating Gli1. We've shown a clear-cut mechanism to link all non-canonical activation of Gli1 through a single pathway, mTOR.

Crosstalk between these two pathways is a challenge, but our experiments showed a combination of the mTOR inhibitor Afinitor (everolimus) and the Hedgehog inhibitor Erivedge (vismodegib) steeply reduced the tumor burden in a mouse model of esophageal adenocarcinoma."

The U.S. Food and Drug Administration (FDA) has approved both drugs for use in other types of cancer.

After examining 107 tissue samples of human esophageal cancer, the researchers found that 87 (81.3%) had a marker of Gli1 activated by Hedgehog and 80 (74.8%) had a marker of mTOR promotion of Gli1.

According to the researchers less than 20% of individuals suffering from esophageal cancer (one of the most aggressive forms of cancer) survive for 5 years. Furthermore, they highlight that since the 1980s, the disease has become more prevalent in the U.S by 5% to 10% each year. Obesity and inflammation are believed to contribute to this increased incidence.

In order to show how mTOR and Hedgehog, both involved in esophageal and other types of cancers, converge on Gli1, the team conducted experiments with cell lines, human tumor samples and mouse models.

Gli1 is a transcription factor - a protein that enters the cell nucleus where it attaches and stimulates other genes. Usually a protein called SuFu attaches to Gli1 at a specific region preventing it from entering the nucleus.

According to Hung, the Hedgehog pathway stimulates a signaling protein called Smoothened (SMO), which prevents SuFu from attaching to Gli1. SMO allows Gli1 to enter the nucleus and activate a variety of genes, including Hedgehog activators.

In January the FDA approved Erivedge (vismodegib) for treatment of metastatic basal cell carcinoma, inhibits SMO. Mutations in the Hedgehog pathway power basal cell carcinoma, however in clinical trials conducted to treat cancers, such as pancreas and ovarian, resistance to SMO inhibitors has emerged.

Hung explained: "We now believe the mTOR pathway is one source of this resistance."

The researchers first conducted a series of experiments with Tumor Necrosis Factor Alpha (TNFa), an inflammatory protein associated to development of esophageal cancer, and discovered that TNFa activates Gli1 via the mTOR pathway by:

Stimulating the kinase S6K1, which binds to phosphate group to Gli1. This attachment prevents phosporylated Gli1 from binding to SuFu.

With SuFu inhibited, the phosphorylated version of Gli1 enters the nucleus and stimulates genes.

In order to identify the presence of phosphorylated Gli1, the researchers developed an antibody which could provide a biomarker of cancer resistance to Hedgehog inhibitors.

They treated mice with esophageal cancer with Erivedge, Afinitor or both and found that the Hedgehog inhibitor Erivedge reduced tumor volume by 40%, while the mTOR inhibitor Afinitor alone had virtually no effect. However, when combined Afinitor and Erivedge reduced tumor volume by 90%.

According to Hung, human trials of the Afinitor and Erivedge combination for esophageal and other cancers could be guided by the antibody for phosphorylated Gli as well as the presence of plain Gli1, which would suggest that both drugs are needed.

Previous studies conducted by other labs suggest that the AKT and MAPK/ERK also stimulate the Hedgehog pathway. Hung and colleagues demonstrate that AKT and ERK, which both stimulate the mTOR pathway, seem to activate Gli1 through phosphorylation of S6K1 and Gli1.

Source: Cancer Cell

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With the advent of temsirolimus and everolimus, both rapamycin derivatives that target mTOR, we now have at our disposal agents that are every bit a part of the therapy repertoire. Unlike erlotinib that targets a specific tyrosine kinase, mTOR is a complex and multifaceted target.

There are actually two separate forms of mTOR, TORC1 and TORC2, and they sit at a critical point in cellular determination. Stimulated by the insulin growth pathway, cells must decide whether they will grow in size or divide. The mTOR proteins participate in this process by regulating protein synthesis and glucose uptake among other functions. In turn, the mTOR pathway is regulated by numerous other factors like AMP kinase and AKT. The current crop of mTOR inhibitors all target TORC1.

New classes of compounds are being developed that inhibit both TORC1 and TORC2. More interesting are the compounds that influence upstream signaling, including phosphoinositol kinase (PI3K) and AKT. What we are coming to learn, however, is that these are not targets but collections of targets. Indeed, the PI3K inhibitors themselves have influence on one, two or all of the distinct classes of phosphoinositol kinases.

Most of the studies to date have used compounds that affect all the classes equally (pan-inhibitors). Pharmaceutical companies are now developing highly selective inhibitors of this fundamental pathway. In addition, duel inhibitors that target both PI3K and mTOR are in clinical trials. What we are coming to realize is the complexity of these pathways.

What may prove more vexing still is their redundancy. One well-established by-product of successful inhibition of mTOR (principally TORC1) is the upstream activity of AKT via a feedback loop. This has the undesirable affect of redoubling mTOR stimulation through the very pharmacological manipulation that was designed to inhibit it. Again, an unintended consequence of a well laid plan.

To unravel the complexities and redundancies of these processes, we have utilized the primary culture platform. It enables us to examine the end result of signal inhibition and dissect disease specific profiles. Using this approach we can partner with collaborators to define the specific operative pathways in each disease entity. Biological complexity is the hallmark of life.

Source: Dr. Robert Nagourney; Rational Therapeutics, Inc.

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Blocking the embryonic signalling pathway, known as Hedgehog (Hh), could form a basis of new treatments. By using drugs to inhibit the Hedgehog signalling, they should be able to increase the effectiveness of chemotherapy and reduce the risk of cancer relapse.

Erivedge (vismodegib) is such a drug that inhibits Hh signaling by targeting the serpentine receptor Smoothened (SMO), and has produced promising anti-tumor responses in clinical studies of cancers driven by mutations in this pathway.

Cancer stem cells (CSCs), are aggressive cells thought to be resistant to current anti-cancer therapies and which promote metastasis, are stimulated via a pathway that mirrors normal stem cell development. Disrupting the pathway, researchers are able to halt expansion of CSCs.

One approach is to force the CSCs into a differentiated state, thereby impairing stem characteristics, such as self-renewal. Interference with the Notch, Wnt, or Hedgehog pathways that are thought to regulate differentiation, are strategies that have been proposed.

Cell-based functional profiling labs have recognized the interplay between cells, stroma, vascular elements, cytokines, macrophages, lymphocytes and other environmental factors. This lead to their focus on the human tumor primary culture microspheroid (microclusters), which contains all of these elements.

In their earlier work, they endeavored to isolate tumor cells from their benign constituents so as to study "pure" tumor cells. As time went on, however, they found that these disaggregated cells were artificially sensitized to the effects of chemotherapy and provided false positive results in vitro.

Early work by Beverly Teicher and Robert Kerbel that examined cells alone and in three-dimensional (3D) structures, lead to the realization that cancer cells inhabit a microenvironment. Functional profiling labs now study cancer response to drugs within this microenvironment, enabling them to provide clinically relevant predictions to cancer patients.

It is their capacity to study human tumor microenvironments that distinguishes them from other lab platforms in the field. And, it is this capacity that enables them to conduct discovery work on the most sophisticated classes of compounds that influence cell signaling at the level of Notch, Hedgehog and Wnt, among others (Gonsalves, F, et al. (2011).

An RNAi-based chemical genetic screen identifies three small-molecule inhibitors of Wnt/wingless signaling pathway (PNAS vol. 108, no. 15, pp. 5954-5963). With this clinically validated platform they are now positioned to streamline drug development and advance experimental therapeutics.

Source: Dr. Robert Nagourney; Rational Therapeutics, Inc.

[url]http://www.rational-t.com/downloads/pdfs/WNT_Inhibitor.pdf

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Targeted therapies have been studied for years, but recent laboratory research is providing robust clues about drugs that might work better in combination, particularly in treating cancers that have become resistant to therapy. That kind of information is behind a novel clinical trial at Georgetown Lombardi Comprehensive Cancer Center that combines cetuximab and lapatinib. Findings from this phase I study will be presented at the American Society of Clinical Oncology (ASCO) annual meeting in Chicago.

Cetuximab works by blocking the epidermal growth factor receptor (EGFR) found on the outside of a cell. In cancers such as colon, head and neck, and lung, when cetuximab stops EGFR signaling, the machinery inside the cell doesn't get the signal to grow, in turn causing it to die. However, cancer cells can become resistant to cetuximab when the EGFR receptor combines with a related receptor HER2 (ErbB2) - which cetuximab can't block. Once again, the cell gets the signal to grow. Lapatinib however blocks HER2 and EGFR from the inside of cancer cells.

"Cancer cells are good at developing ways around our treatments, including new targeted therapies such as cetuximab." says John Deeken, M.D., a medical oncologist at Georgetown Lombardi Comprehensive Cancer Center. "By combining different targeted therapies, we hope to be able to overcome such resistance and turn off the cancer cell signal to grow."

Deeken, an expert in how cells metabolize or process drugs, took the information learned from these recent pre-clinical studies and designed a novel clinical trial - combining cetuximab, which blocks EGFR, with lapatinib which works inside the cell and shuts down HER2. GlaxoSmithKline provided lapatinib for the study and additional financial support for the study.

Cetuximab, marketed as Erbitux, has been approved by the U.S. Food and Drug Administration (FDA) for the treatment of metastatic colorectal cancer and head and neck cancer. Lapatinib, marketed as Tykerb, is FDA-approved for the treatment of some types of breast cancer.

Sixteen patients whose tumors are driven by EGFR were enrolled in the study and received the established dose of cetuximab (intravenously once a week). Lapitinib, a drug taken orally on a daily basis, was given in escalating doses. Twelve of thirteen patients were evaluable for toxicities (side effects). The most common side effects of the combination were rash and diarrhea, both of which can be managed with supportive medications and care.

"While this study isn't designed to evaluate whether or not this combination of drugs works, we have seen some positive signs of clinical activity," Deeken says.

Of nine patients evaluable for response (completed at least two cycles of treatment), two had a partial response (more than 30 percent tumor shrinkage),and two had prolonged stable disease of 2 cycles or more, for a clinical benefit rate of 44 percent.

Phase II studies to test this combination in colon as well as head and neck cancer patients are under development, Deeken says.

References:

In addition to Deeken, other investigators from the Lombardi Phase I/Developmental Therapeutics Program involved in the study include Hongkun Wang, Ph.D., Jimmy Hwang, M.D., John Marshall, M.D., Deepa Subramaniam, M.D., Aiwu Ruth He, M.D., Ph.D., Louis M. Weiner, M.D., Rosemarie Hardesty, R.N., Ken Steadman, Michael J. Pishvaian, M.D., Ph.D. None of the authors report personal financial interests related to the study.

Georgetown University Medical Center

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Clinical Benefit Rate (CBR) and Disease Control Rate (DCR) are defined as the percentage of patients with advanced or metastatic cancer who have achieved complete response, partial response and stable disease to a therapeutic intervention in clinical trials of anticancer agents. CBR and DCR are commonly reported in many clinical trials in abstracts, papers, meeting presentations and media releases. The frequent use of these measures of drug activity presents the question of whether CBR and DCR are useful additional endpoints in early clinical trials, and if they can reasonably predict the success of an agent in subsequent, adequately powered, randomized trials. There are no comprehensive analyses to demonstrate that CBR or DCR add to the value of traditional response/activity endpoints in early clinical trials. Data from phase II clinical trials in which the CBR or DCR are reported suggest that CBR or DCR provides ambiguous information that likely exaggerates the anticancer activity of the therapy. The terms 'disease control' and 'clinical benefit' in the context of non-randomized trials are themselves disingenuous because neither tumor regression nor stable disease, defined without any consideration of duration of effect or reduction of symptoms appropriate for the specific patient population, are evidence of these endpoints in an individual patient (Curr Opin Investig Drugs. 2010 Dec;11(12):1340-1).

Reporting disease control rates or clinical benefit rates in early clinical trials of anticancer agents: useful endpoint or hype?

[url]http://www.ncbi.nlm.nih.gov/pubmed/21268434