HER2 Support Group Forums - View Single Post - Embryonic signal drives pancreatic cancer and offers a way to kill it

gdpawel · 11-07-2011, 07:08 PM

Rich

This looks similar to research being done by an international team from Monash, Stanford and John Hopkins universities which represents not just the potential for new drugs but also a novel way of approaching cancer treatment.

The study, published in the "Nature Medicine" journal, 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.

Blocking the embryonic signalling pathway, known as Hedgehog (Hh), could form basis of new SCLC 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.

Vismodegib (GDC-0449) 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.

11-07-2011, 07:08 PM	#2
gdpawel Senior Member Join Date: Aug 2006 Location: Pennsylvania Posts: 1,080	Hedgehog signaling is a potent regulator of angiogenesis Rich This looks similar to research being done by an international team from Monash, Stanford and John Hopkins universities which represents not just the potential for new drugs but also a novel way of approaching cancer treatment. The study, published in the "Nature Medicine" journal, 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. Blocking the embryonic signalling pathway, known as Hedgehog (Hh), could form basis of new SCLC 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. Vismodegib (GDC-0449) 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.