Cancer Stem Cell Research Leads to Clinical Trials


Dennis Slamon and Zev Wainberg from the UCLA Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research have been awarded a Disease Team Therapy Development award to begin clinical trials in human patients early in 2014.

In this clinical trial, Slamon and Wainberg will test a new drug that targets cancer stem cells. This drug was developed by research and development over the last decade on the cancer stem cell hypothesis. The cancer stem cell hypothesis predicts that proliferating stem cells are the main drivers of tumor growth and are also resistant to standard cancer treatments.  This new drug, CFI-400945, has prevented cancer growth in an extensive series of laboratory animal tests.

An important extension of the cancer stem cell hypothesis is that cancer stem cells inhabit a particular niche that prevents anticancer drugs from reaching them. Alternatively, tumors become resistant to cancer drugs by a process called “cell fate decision,” in which some cancer stem cells are killed by chemotherapy, but other cells replace them and repopulate the tumor. This tumor repopulation is the main reason for cancer recurrence.

The new anticancer drug to be tested in this clinical trial targets the “polo-like kinase 4.” Inhibition of this enzyme effectively blocks cell fate decisions that cause cancer stem cell renewal and tumor cell growth. Thus inhibition of this enzyme effectively stops tumor growth.

This clinical trial will test this novel chemotherapeutic agent in patients to establish the safety of the drug. After these initial safety tests, the trial will quickly proceed to further clinical tests. “We are excited to continue to test this drug in humans for the first time,” said Wainberg. Slamon, Wainberg and others will also look for biological markers to determine how well their drug is working in each patient.

The US Food and Drug Administration approved the Investigational New Drug (IND) for this drug trial. Also, Health Canada, the Canadian government’s therapeutic regulatory agency, also approved this trial. These approvals are part of an international effort to bring leading-edge stem cell science to patients.

Adult Stem Cells Suppress Cancerous Growth While Dormant


William Lowry and his postdoctoral fellow Andrew White at UCLA’s Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research have discovered the means by which particular adult stem cells suppress their ability to trigger skin cancer during their dormant phase. A better understanding of this mechanism could provide the foundation to better cancer-prevention strategies.

This study was published online Dec. 15 in the journal Nature Cell Biology. William Lowry, Ph.D. is an associate professor of molecular, cell and developmental biology in the UCLA College of Letters and Science.

Hair follicle stem cells are those tissue-specific adult stem cells that generate the hair follicles. Unfortunately, they also are the cell population from which cutaneous squamous cell carcinoma, a common skin cancer, begins. However, these stem cells cycle between active periods, when they grow, and dormant periods, when they do not grow.

Diagram of the hair follicle and cell lineages supplied by epidermal stem cells. A compartment of multipotent stem cells is located in the bulge, which lies in the outer root sheath (ORS) just below the sebaceous gland. Contiguous with the basal layer of the epidermis, the ORS forms the external sheath of the hair follicle. The interior or the inner root sheath (IRS) forms the channel for the hair; as the hair shaft nears the skin surface, the IRS degenerates, liberating its attachments to the hair. The hair shaft and IRS are derived from the matrix, the transiently amplifying cells of the hair follicle. The matrix surrounds the dermal papilla, a cluster of specialized mesenchymal cells in the hair bulb. The multipotent stem cells found in the bulge are thought to contribute to the lineages of the hair follicle, sebaceous gland, and the epidermis (see red dashed lines). Transiently amplifying progeny of bulge stem cells in each of these regions differentiates as shown (see green dashed lines).
Diagram of the hair follicle and cell lineages supplied by epidermal stem cells. A compartment of multipotent stem cells is located in the bulge, which lies in the outer root sheath (ORS) just below the sebaceous gland. Contiguous with the basal layer of the epidermis, the ORS forms the external sheath of the hair follicle. The interior or the inner root sheath (IRS) forms the channel for the hair; as the hair shaft nears the skin surface, the IRS degenerates, liberating its attachments to the hair. The hair shaft and IRS are derived from the matrix, the transiently amplifying cells of the hair follicle. The matrix surrounds the dermal papilla, a cluster of specialized mesenchymal cells in the hair bulb. The multipotent stem cells found in the bulge are thought to contribute to the lineages of the hair follicle, sebaceous gland, and the epidermis (see red dashed lines). Transiently amplifying progeny of bulge stem cells in each of these regions differentiates as shown (see green dashed lines).

White and Lowry used transgenic mouse models for their work, and they inserted cancer-causing genes into these mice that were only expressed in their hair follicle stem cells. During the dormant phase, the hair follicle stem cells were not able to initiate skin cancer, but once they transitioned into their active period, they began growing cancer.

Dr. White explained it this way: “We found that this tumor suppression via adult stem cell quiescence was mediated by PTEN (phosphatase and tensin homolog), a gene important in regulating the cell’s response to signaling pathways. Therefore, stem cell quiescence is a novel form of tumor suppression in hair follicle stem cells, and PTEN must be present for the suppression to work.”

Retinoids are used to treat certain types of leukemias because they drive the cancer cells to differentiate and cease dividing. Likewise, understanding cancer suppression by inducing quiescence could, potentially, better inform preventative strategies for certain patients who are at higher risk for cancers. For example, organ transplant recipients are particularly susceptible to squamous cell carcinoma, as are those patients who are taking the drug vemurafenib (Zelboraf) for melanoma (another type of skin cancer). This study also might reveal parallels between squamous cell carcinoma and other cancers in which stem cells have a quiescent phase.