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New way to halt small cell lung cancer


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Scientists have discovered a mechanism which they claim causes an aggressive type of lung cancer to re-grow following chemotherapy thus offering hope for new therapies.

An international team from Monash, Stanford and John Hopkins universities, says that the discovery represents not just the potential for new drugs but also a novel way of approaching cancer treatment.

Professor Neil Watkins of Monash University said while many current cancer treatments focus on shrinking existing tumors, this research had a different focus.

"Some aggressive types of cancer respond very well to chemotherapy, but then the real challenge is to stop the tumour coming back. That`s what we investigated," he said.

Between 15 and 20 per cent of lung cancer cases are an extremely aggressive type known as small cell lung cancer (SCLC) that usually responds well to chemotherapy, but regrows and is then less responsive to the treatment.

The study showed that the regrowth of SCLC cells could be blocked by a drug that targets growth signals, which, in healthy cells, control organ development and repair.

Professor Watkins said that blocking the signalling pathway, known as "Hedgehog," could form basis of new SCLC treatments.

"This discovery gives us important clues for designing new treatment approaches. By using drugs to inhibit the Hedgehog signalling, we should be able to increase the effectiveness of chemotherapy and reduce the risk of cancer relapse," he said.

The findings have been published in the Nature Medicine journal.

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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.

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Small cell lung cancer (SCLC), a highly aggressive neuroendocrine subtype of lung cancer and frequently lethal, uses an embryonic signaling pathway to promote its growth. This signaling pathway is known as the Hedgehog (Hh) pathway, and its normal function is to regulate organ formation and regulate progenitor cells in embryos and in some adult tissues.

SCLC is characterized by abnormal activation of this pathway which can be specifically inhibited by cyclopamine, a naturally occurring compound. Use of cyclopamine specifically inhibits the growth of SCLC, and suggests a potential way to exploit this pathway for novel therapeutic strategies.

These strategies could ultimately involve cyclopamine, and other novel inhibitors of Hedgehog pathway, to treat SCLC. Approximately 200,000 people a year die from lung cancer in the United States, 25% of these from SCLC. After initial responses to chemotherapy, the vast majority of patients relapse and die within twelve months.

Vismodegib (GDC-0449) is 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.


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By D. Neil Watkins, MBBS, PhD, FRACP, and Craig D. Peacock, PhD

Small cell lung cancer (SCLC) is a highly aggressive neuroendocrine tumor of the airway epithelium with a 5-year survival rate of less than 5%. At least half of cases are highly responsive to cytotoxic chemotherapy, only to recur within 12 months. Despite the introduction of several new cytotoxic agents, the outcome of this disease remains essentially unchanged. It is proposed that progress in the treatment of SCLC may require new approaches in how this tumor is viewed.

SCLC is definitively a carcinoma, but many of its phenotypic and biologic features closely resemble primitive neuroectodermal tumors, such as medulloblastoma (MB). MB might serve as a model to rethink how SCLC is viewed. MB is frequently curable, and, unlike SCLC, displays little in the way of genomic instability.

However, marked similarities in the expression of neural markers, transcription factors, and activation of embryonic signaling pathways between the two tumors suggest that MB might serve as a useful model for developing alternate strategies for treating SCLC.

MB frequently relies on Notch and Hedgehog (Hh) signaling to maintain its progenitor hierarchy. Small molecules targeting these pathways inhibit clonal capacity and self-renewal in both MB and SCLC, and may do so by selectively targeting progenitor or stem-cell compartments in each tumor.

These ideas suggest that inhibition SCLC recurrence by targeting progenitor cells in SCLC might represent a new way to approach treatment.

Targeting the hedgehog pathway

The most common way to target this pathway is modulate SMO. Antagonist and agonist of SMO have already shown to effect the pathway regulation downstream. The most clinically advanced SMO targeting agents are cyclopamine. Itraconazole (Sporanox) has also been shown to target SMO through a mechanism distinct from cyclopamine and vismodegib.

PTCH and Gli3 (5E1) antibodies are also a way to regulate the pathway. A downstream effector and strong transcriptional activator siRNA Gli1 has been used to inhibit cell growth and promote apoptosis. Arsenic trioxide (Trisenox) has also been shown to inhibit hedgehog signaling by interfering with Gli function and transcription.

http://www.asco.org/ASCOv2/Home/Educati ... lung09.pdf

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The Hedgehog signaling pathway is a target of growing interest in the oncology community. It represents a new way of understanding and potentially attacking the progression and reoccurrence of cancer. The Hedgehog pathway is normally active during embryonic development and regulates tissue and organ formation.

When abnormally activated in adults the Hedgehog pathway is believed to play a central role in allowing the proliferation and survival of cancer cells, including pancreatic cancer, prostate cancer, small cell lung cancer, breast cancer, hematologic cancers, skin cancers, and certain brain cancers.

In addition, recent evidence points to a potentially important role for the Hedgehog pathway in tumor progenitor cells. Tumor progenitor cells are resistant to standard anti-cancer agents and radiation, and are therefore suspected to be responsible for disease relapse following treatment with conventional therapeutic agents.

List of Related Hedgehog Pathway Cancers

Mutation Driven



Nevoid Basal Cell Carcinoma Syndrome (NBCCS)

Basal Cell Carcinoma

Gorlin Syndrome

Ligand Driven

Breast Cancer

Esophageal Cancer

Gastric Cancer


Pancreatic Cancer

Prostate Cancer

Small-Cell Lung Cancer (SCLC)

Colon Cancer

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Small-cell lung cancer: an unusual therapeutic approach with more than 10-year overall survival. Case report and review of the literature.

Samelis GF, Ekmektzoglou KA, Xanthos T, Zografos GC.

Department of Medical Oncology, Hippocratio General Hospital, Athens, Greece.


Small-cell lung cancer is the most aggressive lung cancer, with a dismal prognosis. The authors present a case report of a patient with limited-stage small-cell lung cancer who underwent a thoracotomy for diagnostic purposes, with the diagnosis being made after surgical excision. Combination chemotherapy remains the cornerstone of treatment for both limited and extensive disease. Radiotherapy has been established as an adjunct to chemotherapy in limited-stage disease, while in extensive-stage disease it is mostly reserved for the treatment of brain metastases. As for surgery, the potential benefits of resection are predominantly seen in patients who present with a solitary pulmonary nodule. Since small-cell lung cancer becomes highly resistant to chemotherapy, second-line chemotherapeutic schemes are used for disease progression, with topotecan being the highlighted agent. Despite the unusual therapeutic approach, where surgery was preferred over the standard diagnostic and staging procedures, the patient's more than ten years' survival makes this case presentation a very interesting one.

Tumori. 2008 Jul-Aug;94(4):612-6. PMID:18822705[PubMed - indexed for MEDLINE]

http://www.tumorionline.it/allegati/003 ... 616%29.pdf

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SCLC tumors with a protein called FGF-2 (fibroblast growth factor) are known to be less likely to respond to treatment. A tumor with this FGF-2 protein will be resistant to just about all chemotherapy.

However, FGF is one of about 15 proteins known to activate endothelial cell growth and movement. At a critical point in the growth of a tumor, the tumor sends out signals to the nearby endothelial cells to activate new blood vessel growth. Two endothelial growth factors, VEGF and basis fibroblast growth factor (bFGF), are expressed by many tumors and seem to be important in sustaining tumor growth.

About 15 proteins are known to activate endothelial cell growth and movement, including angiogenin, epidermal growth factor, estrogen, fibroblast growth factors (acidic and basic), interleukin 8, prostaglandin E1 and E2, tumor necrosis factor-, vascular endothelial growth factor (VEGF), and granulocyte colony-stimulating factor. Some of the known inhibitors of angiogenesis include angiostatin, endostatin, interferons, interleukin 1 ( and ß), interleukin 12, retinoic acid, and tissue inhibitor of metalloproteinase-1 and -2. (TIMP-1 and -2).

At a critical point in the growth of a tumor, the tumor sends out signals to the nearby endothelial cells to activate new blood vessel growth. Two endothelial growth factors, VEGF and basic fibroblast growth factor (bFGF), are expressed by many tumors and seem to be important in sustaining tumor growth.

The European Molecular Biology Organization Journal (2006)

http://www.mendeley.com/research/fgf2-p ... nd-s6k2-1/

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In a review in Science, a University of Rochester Medical Center researcher sorts out the controversy and promise around a dangerous subtype of cancer cells, known as cancer stem cells, which seem capable of resisting many modern treatments.

The article proposes that this subpopulation of malignant cells may one day provide an important avenue for controlling cancer, especially if new treatments that target the cancer stem cell are developed and combined with traditional chemotherapy and/or radiation.

"The fact that these concepts are steadily making their way into the clinic is exciting, and suggests that the recent interest in cancer stem cells may yield beneficial outcomes in potentially unexpected ways," wrote co-authors Craig T. Jordan, Ph.D., professor of Medicine at URMC and director of the James P. Wilmot Cancer Center Translational Research for Hematologic Malignancies program; and Jeffrey Rosen, Ph.D., the C.C. Bell Professor of Molecular and Cellular Biology and Medicine at Baylor College of Medicine.

Cancer stem cells (CSCs) are a hot topic in the scientific community. First identified in 1994 in relation to acute myeloid leukemia, CSCs have now been identified in several solid tumors in mice as well. Scientists who study CSCs believe they have distinct properties from other cancer cells, and may be the first cells to undergo mutations.

Research from the past 10 years suggests that because CSCs may be the root of cancer, they also might provide a new opportunity for a treatment. Jordan and a group of collaborators, for example, are testing a new drug compound based on the feverfew plant that demonstrates great potential in the laboratory for causing leukemia CSCs to self destruct.

Another new approach, the authors said, is the use of chemical screens to search drug libraries for already approved agents that may target CSCs, or make resistant tumor cells more sensitive to chemotherapy and radiation.

Cancer stem cell biologists hypothesize that any treatment that targets the source of origin rather than simply killing all cells, healthy and malignant, would be an improvement over most conventional therapies.

Some scientists, however, are uncertain if CSCs have unique biological properties or any relevance to treatment, the authors noted. What is more likely to fuel cancer, other studies have found, are unfavorable factors in the neighboring cells surrounding the tumor, such as mutated genes, proteins that encourage cell growth, and a poor immune system, for instance.

The most challenging issue facing CSC biologists is that the number and type of cancer stem cells can vary from patient to patient. In some tumor samples, for example, CSCs are rare while in others they constitute a large portion of the tumor mass, the authors said.

To understand why CSCs are so variable, investigators are trying to determine what genes and pathways are responsible for activating cancers that have a poor prognosis, and whether these cancers also have a higher frequency of CSCs.

"Whether the cancer stem cell model is relevant to all cancers or not," they wrote, "it is clear that we need new approaches to target tumor cells that are resistant to current therapies and give rise to recurrence and treatment failure."

An unexpected benefit of so much attention on normal stem cells is that it has stimulated research in areas not previously the focus of cancer therapies, Jordan and Rosen said.

For example, pathways known to be important for normal stem cell self-renewal, such as the Wnt, Notch and Hedgehog(Hh) pathways, are now of increased interest due to their potential role in CSCs. The first clinical trial using an agent to block the Notch pathway in combination with chemotherapy for breast cancer has begun.

The authors conclude by spotlighting the pressing need for preclinical models to test appropriate doses and combinations of CSC therapies before they can move into human clinical trials.

Source: University of Rochester Medical Center

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By NYU Langone Medical Center Apr 12, 2011

Researchers from the Cancer Institute at NYU Langone Medical Center have identified three novel small molecules that interrupt a crucial cellular communication pathway that regulates many aspects of development and cancer. The finding, published in the April 12, 2011 issue of the Proceedings of the National Academy of Sciences and featured on its cover, could provide the basis for innovative therapies for colorectal cancer and other diseases associated with aberrations in this pathway.

“Our study demonstrates that the three newly identified compounds are capable of blocking cell proliferation in cancerous human tumor biopsy cells,” said Ramanuj DasGupta, PhD, assistant professor of Pharmacology at NYU School of Medicine and the NYU Cancer Institute, and the scientific director of the NYU RNAi Core Screening Facility.

Dr. DasGupta and his colleagues identified the molecules as inhibitors of the Wnt signaling pathway. This pathway is of special interest to scientists because it controls many biological processes by promoting cell-to-cell communication. Many previous studies have shown that cancers in the liver, breast, skin, and especially the colon, are associated with abnormal signaling activity in this pathway. However, it has been difficult to find potential therapeutic agents aimed at the Wnt pathway.

“These molecules hold a lot of promise towards future Wnt-based drug development for cancer treatments,” says Dr. DasGupta. “They may allow the compounds to be used for specific therapeutic purposes in humans to induce the death of Wnt-dependent or Wnt –addicted cancer cells and tumor tissues without affecting the growth and proliferation of normal healthy cells.”

The scientists demonstrated that the molecules suppressed the activity of the Wnt signaling pathway—without disrupting other cellular functions—in human colon cancers from biopsies, in colon cancer cell lines, and in a mouse tumor-xenograft model. In all instances, the inhibitors stopped the proliferation of cancerous cells in the laboratory dish or in the mouse.

“To date, no therapies for the control of Wnt-driven tumors have been available for colon cancer, lung cancer, leukemia, and other forms of the disease caused by mutations in the Wnt pathway,” said Robert A. Nagourney, MD, of Rational Therapeutics in Long Beach, California, who is one of the study’s authors. “The findings in our human tissue model give us real hope that these compounds will have important implications in future clinical therapy and the development of an effective Wnt inhibitor.”

The Wnt pathway is complex and only partially understood. Wnt genes bind to receptors on the surface of cells, provoking a reaction (or a “signaling cascade”) within the cell that ultimately allows various “downstream effector proteins” to go into action. One of these proteins, called β catenin, moves into the nucleus and oversees the activation of genes often associated with cell proliferation and other processes.

In the study, the researchers used an innovative, integrated screening platform combining RNA interference (RNAi) -technology and high-throughput chemical genetic screening to examine the potency of 14,977 compounds on the activity of the Wnt pathway. This targeted screening methodology helped identify the three promising novel inhibitors capable of blocking Wnt target genes in various mammalian cancer cell lines including human colon and breast cancer cells. Foster C. Gonsalves, PhD, first author of the study and post-doctoral fellow in Dr. DasGupta’s lab, helped develop this technique.

“While more exploratory research of these promising compounds is needed, these small molecules identified in the RNAi screens can serve as prototypes for the development of future antitumor drugs targeting the Wnt signaling pathway in different Wnt-associated cancers,” says Dr. DasGupta. “Similar RNAi-based integrated screening technology should be widely applicable to a variety of other signaling pathways implicated in human disease.”

This study highlights the strength of high-throughput RNAi-based genome-wide or genome-scale modifier screens currently being performed at NYU’s RNAi Screening Facility, according to Dr. DasGupta. The state-of-the-art functional genomic approach continues to help answer basic biological questions in cellular signaling and better define the Wnt pathway, he says.

Along with Dr. DasGupta and Dr. Gonsalves, the authors of the study include Keren Klein, Shauna Katz and Timothy Cardozo from NYU School of Medicine, and Brittany B. Carson and Anthony C. Brown from Weill Cornell Medical College.

The study was supported by grants from the National Institutes of Health, the Department of Defense, and The Helen L. and Martin S. Kimmel Center for Stem Cell Biology at NYU School of Medicine.

The April 12 issue of PNAS (Proceedings of the National Academy of Sciences) features a lead article by investigators at NYU, Cornell and Rational Therapeutics, on the identification of three compounds that inhibit the important cell signaling pathway known as WNT (catenation of Wg and Int).

The WNT signaling pathway was originally described in fruit flies as a determinate of wing shape. It was subsequently shown to be an important factor in human stem cell differentiation. Thereafter, its role in cancer was described.

Certain colon cancers associated with a familial syndrome have a mutation in the WNT pathway. This results in an extremely high incidence of colon cancer. It is known that lung cancers, breast cancers, leukemias and lymphomas may share this pathway.

To date, there have been no clinical therapies available to treat WNT-driven tumors. Recognizing the importance of this pathway, the investigators at NYU and Cornell used a technology known as small interfering RNA (SIRNA) to shut down the WNT signal. They then screened 14,000 known chemicals for activity that mimicked the SIRNA effect. Three compounds were identified.

When the compounds showed activity in cell-lines that were WNT addicted, the investigators at NYU provided the compounds to Rational Therapeutics where they applied the EVA-PCD (functional profiling) technique to measure activity in human tumor samples.

The results confirmed activity and showed that several colon cancers, as well as other tumor types, had favorable profiles. The compounds were not uniformly effective, indicating that they were not simply toxins. Instead, they appeared to selectively injure cells that we assume are driven by WNT-related events.

The beauty of this study represents the introduction of a new paradigm of drug development. Following the elegant and highly sophisticated high throughput method employed by investigators at NYU and Cornell, these compounds were put to the very practical test of human relevance.

The identification of activity in human tissues at concentrations similar to those associated with other classes of drugs, suggest that these novel compounds may have promise with these heretofore-untreatable cancers. This highly productive collaboration could prove a new model for the development of effective new therapies.

PNAS April 12, 2011 vol. 108 no. 15 5929-5930


http://robertanagourney.wordpress.com/2 ... velopment/

http://www.rationaltherapeutics.com/dow ... ibitor.pdf

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Prognostically orientated multimodality treatment including surgery for selected patients of small-cell lung cancer patients stages IB to IIIB: long-term results of a phase II trial.

Eberhardt W, Stamatis G, Stuschke M, Wilke H, Müller MR, Kolks S, Flasshove M, Schütte J, Stahl M, Schlenger L, Budach V, Greschuchna D, Stüben G, Teschler H, Sack H, Seeber S.


Following mediastinoscopy, a prognostically orientated multimodality approach was chosen in selected small-cell lung cancer (SCLC) patients with hyperfractionated accelerated chemoradiotherapy (Hf-RTx) and definitive surgery (S). Stage IB/IIA patients had four cycles of cisplatin/etoposide (PE) and surgery. Stage IIB/IIIA patients had three cycles PE followed by one cycle concurrent chemoradiation including Hf-RTx and surgery. Most stage IIIB patients were not planned for surgery and had CTx followed by sequential RTx or one cycle concurrent CTx/RTx. Of 46 consecutive patients (stage IB six, IIA two, IIB/IIIA 22, IIIB 16) 43 (94%) showed an objective response. Twenty-three of patients (72%) planned for inclusion of S were completely resected (R0) (IB 6/6, IIA 2/2, IIB/IIIA 13/22, IIIB 2/2). Overall toxicity was acceptable--one patient died of septicaemia, no perioperative deaths occurred. Median follow-up of patients alive (n = 21) is 52 months (30+ - 75+). Median survival and 5-year survival rate of all patients are 36 months and 46%, in R0 patients 68 months and 63% (R0-IIB/IIIA/IIIB: not yet reached and 67%). This multimodality treatment including surgery proved highly effective with 100% local control and remarkable long-term survival after complete resection, even in locally advanced SCLC stages IIB/IIIA patients.

Source: Department of Internal Medicine (Cancer Research), West German Cancer Center, University of Essen Medical School. Br J Cancer. 1999 Dec;81(7):1206-12.

http://www.ncbi.nlm.nih.gov/pmc/article ... 90830a.pdf

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