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Feature Articles : Oct 15, 2010 (Vol. 30, No. 18)

Stem Cell Therapies Make Steady Progress

Preclinical Development of ESC-, iPSC-, CSC-, and CLSC-Derived Products Moves Along Briskly
  • Josh P. Roberts

Stem cells are many things to many people—a product of an errant procedure, the origin of cancer, a naturally occurring source of unlimited healing potential, a Frankenstein-like creation of virally infected cells, or a political football.

CHI’s inaugural “Stem Cells in Drug Discovery and Development,” to be held next month in San Diego, will bring together scientists with broad interests in stem cells of all stripes—embryonic stem cells (ESCs), induced pluripotent stem cells (iPSCs), adult (somatic) stem cells, and even cancer stem cells (CSCs) and cancer-like stem cells (CLSCs). These cells can be kept pluripotent or forced to differentiate, made into cell lines, used to screen therapeutics, or put into patients.

One of the biggest reasons that compounds fail, or are pulled from the market, is their adverse effect on the heart, says Peter Sartipy, Ph.D., senior principal scientist at Cellartis. Yet in most cases the substances never even come into contact with human tissue until they’re ready for the first clinical trial. Human cardiomyocytes are not available, and “there really is no immortalized human cardiomyocyte cell line today.”

Cellartis is in the business of creating specialized cells from undifferentiated stem cells under feeder-free conditions. “We’re putting a lot of effort into further refining these products and making a lot of progress with processes for large-scale production of these cells,” Dr. Sartipy says, “because that’s really one of the bottlenecks at the moment.” At the meeting, Dr. Sartipy will discuss how to culture and scale-up human pluripotent cells and also highlight differentiation of those cells into cardiomyocytes and hepatocytes.

ESC-derived cardiomyocytes behave very similarly to human cells. Yet the cells that have been derived to date—by Cellartis and others—display more of an embryonic than an absolute adult phenotype. “They are still useful, the functionality that they display is still good.” Dr. Sartipy will show examples of how they “can be used to interrogate cells’ responses when they are exposed to various types of compounds, and to assess toxicity or safety issues in the drug discovery process.” These will be compared with popular in vitro models such as rabbit Purkinje fibers.

Dr. Sartipy will share some unpublished data regarding ESC-derived hepatocytes, illustrating their use in toxicity testing. These cells display many markers and functions of a primary hepatocyte. “The challenge today is mainly to make the cells metabolically active to the same level.”

A big advantage of ESC-derived cells is that you can repeatedly generate new cells from the same genetic background or create libraries of different stem cell lines with different genetic backgrounds. “Because there is a difference between how individuals in the population metabolize drugs, you can generate functional cells from appropriate lines and make a good assay platform.”

Several talks will be presented on high-content screening of stem cells themselves, including one done in collaboration with Cellartis. Paul Andrews, Ph.D., of the University of Dundee, will present data from a 22,500 compound screen of fully pluripotent ESCs for promoters of cell survival.

Others use high-throughput screening techniques to find compounds to drive the fate of stem cells.

Most tissues in the body have adult stem cells (or restricted progenitor cells) that can give rise to additional cells in that organ, points out Tom Novak, Ph.D., senior vp of R&D for Fate Therapeutics.  “We aim to identify those cells and set up screens that allow us to find the modulators of their behavior.

Fate’s CSO, Dan Shoemaker, Ph.D., will present data from the company’s efforts to find small molecules or biologics that  modulate the behavior of resident adult stem cells. He will “explore using gene-expression technology with novel selection and visualization tools to confirm and monitor cell state to establish new stem cell screening paradigms.”

Yet the company is not in the business of cell therapy. “What we would administer to a patient is a much more typical drug—a small molecule or a biologic—and not the cells themselves,” explains Dr. Novak. The aim is to get endogenous adult stem cells to proliferate and differentiate in vivo to replace tissue lost to aging or disease.

“We envision delivering drugs to the patient, whether it’s local administration for formation of new bone in localized areas or systemic in other disease cases. The key to this is knowing that the cells that you’re using for your screens are as closely matched as possible to the endogenous adult stem cells.”

Other presenters will be discussing their own efforts to use differentiated stem cells for toxicity screening. Roche’s Joshua Babiarz, Ph.D., for example, is slated to talk about his successes using iPSC-derived cardiomyocytes for cytotoxicity and electrophysiological studies, while Xianmin Zeng, Ph.D., from the Buck Institute for Age Research will discuss her work differentiating ESCs and iPSCs into neural stem cells, and their use in screening for neurotoxic and neuroprotective effects.

Tumor-Initiating Cells

Cancer stem cells (also known as tumor-initiating cells) are implicated in tumor progression, metastasis, and recurrence. Like normal adult stem cells, CSCs are rare, self-renew, and can reconstitute the tissue from which they are derived. And perhaps because they are slow cycling, they are also notoriously resistant to standard therapies.

The Wnt signaling pathway has been implicated in cancer for 30 years, says Sanjeev Satyal, Ph.D., director of cancer biology at OncoMed Pharmaceuticals. The company has identified what it says are perhaps the first therapeutic agents that target that pathway.

According to Dr. Satyal, the Wnt antagonist that OncoMed expects to have in clinical trials next year is fairly unique in that its mechanism of action works by causing differentiation of the cancer stem cells. “A lot of drugs exist out there and they’re just basically sledgehammers that target the bulk of the tumor but do an inefficient job of causing differentiation.”

The question of what exactly is a “cancer stem cell” plagues academic clinicians like Johns Hopkins’ William Matsui, M.D. “Besides tumorogenicity, what other properties might these things have? Are they responsible for metastatic disease? Or progression of cancers? Are they responsible for chemoresistence? Are they derived from normal stem cells? Do mature tumor cells de-differentiate to make these things? Are they mesenchymal in phenotype with an epithelial tumor?

“All those things are questions that have not been adequately addressed. It’s likely that the answers to those questions are probably different for different diseases.” This leads to confusion in the field, and sometimes resistance to the cancer stem cell concept itself.

The problem is especially evident when designing a clinical trial. Unlike going after a target like BRAF or PI3 kinase to eliminate a tumor, it’s “like you’re testing a novel compound within the context of a novel hypothesis—the foundation is unclear,” Dr. Matsui says. “So it becomes even doubly difficult to do these kinds of trials.”

Whether the cells she derives in the lab are true cancer stem cells is a question that doesn’t seem to bother MacroGenics’ senior vp for stem cell research, Jennie Mather, Ph.D., Raven Biotechnologies, which Dr. Mather founded, developed techniques to isolate and expand stem-like cells from various cancers, amassing a portfolio of CSLC lines (along with a host of monoclonal antibodies that target them). When Raven was purchased by MacroGenics in 2008, these formed the basis of the merged company’s cancer stem-like cell platform.

MacroGenics has a strong antibody-engineering program, allowing it to create “dual-specificity antibody-like therapeutic proteins capable of targeting multiple different epitopes with a single recombinant molecule,” according to the company. Several antibody-based drug candidates, discovered and developed using CSLCs, are presently undergoing preclinical evaluation,” notes CEO Scott Koenig, M.D., Ph.D.