TRAIL selectively kills tumor cells by inducing a form of cell death termed apoptosis.
TRAIL is a natural molecule which is made and expressed on the cell surface of immune cells whose mission involves among other things killing abnormal or malignant tumor cells including myeloma cells. TRAIL which stands for “Tumor Necrosis Factor Related Apoptosis Inducing Ligand” is a member of a family of molecules including Tumor Necrosis Factor and Fas ligand which have potent anti-tumor activity. Unlike Tumor Necrosis Factor or Fas ligand which have proved to be very toxic molecules when given to animals, TRAIL has been successfully administered to rodents and primates. While these animal models have provided encouragement about the prospects of TRAIL being tolerated by humans, several groups recently reported that certain forms of TRAIL may be toxic to human liver and neurological tissues and therefore future clinical trials of TRAIL in patients should proceed with caution. Preliminary reports suggest that the form of TRAIL which is being contemplated for the first human therapy trials sometime in 2001, termed “Apo2L”, may be less or non-toxic to human liver and neurological tissues, though this finding remains to be conclusively established.
TRAIL works to kill malignant but not normal cells by differentially binding to a family of receptors on normal and malignant cells. Tumor cells and many normal cells express “death inducing receptors” termed DR4 and DR5. Normal cells are thought to protect themselves from the effects of TRAIL by expressing “decoy” receptors termed DcR1 and DcR2 which compete away TRAIL from DR4 and DR5 receptors. Ongoing studies in several laboratories including ours are also clarifying other mechanisms by which normal cells are protected from the effects of TRAIL. When bound to the DR4 and DR5 receptors, TRAIL transmits a signal which activates a host of proteins, including caspase 8, which leads to a form of cell death termed apoptosis wherein the DNA of a cell begins to break apart and the nucleus undergoes a process known as condensation. Unlike Fas ligand, TRAIL induced apoptotic cell death is not blocked by interleukin-6 , a secreted protein which is a potent growth and survival factor for myeloma cells and which circulates at elevated levels in many myeloma patients.
TRAIL is a potent inducer of cell death in myeloma cells including myeloma cells which are resistant to chemotherapy and steroids.
In studies by our group which will be updated at the American Society of Hematology meeting in San Francisco in December 2000, the effect of TRAIL was examined on cultured human myeloma cells. TRAIL induced extensive apoptotic cell death of tumor cells taken from 5 of 5 myeloma patients, as well as 11 of 16 cultured myeloma cell lines. These cell lines included myeloma cells which were sensitive and resistant to dexamethasone, a steroid commonly used to treat myeloma patients, along with various chemotherapeutic drugs, including Adriamycin, Melphalan, and Mitoxantrone which are used to treat myeloma patients. The results of these studies suggest that TRAIL is able to overcome drug resistance of myeloma cells to steroids and chemotherapeutic agents. In addition to examining the effect of TRAIL on myeloma cells growing in culture, we also examined the effect of TRAIL on human myeloma tumors (termed plasmacytomas) engrafted in mice. As part of these studies, mice received daily injections of TRAIL for 14 days and plasmacytoma measurements were taken every other day. These studies showed that TRAIL was well tolerated by the mice, and significantly suppressed the growth of engrafted human plasmacytomas compared to mice receiving saline injections. The results of these studies have been submitted for publication.
Adriamycin and agents which block the regulatory protein NFkß sensitize myeloma cells to TRAIL induced apoptotic cell death.
Since in the above studies certain myeloma cell lines were resistant to the effects of TRAIL, we also examined the possibility of reversing TRAIL resistance in myeloma cells by pretreating resistant tumor cells to TRAIL with various chemotherapeutic agents. Adriamycin, a drug commonly used to treat myeloma patients as part of the “VAD” regimen, significantly increased the activity of TRAIL against several myeloma cell lines. Interestingly, Adriamycin increased expression of the TRAIL death receptor DR5 present on the surface of myeloma cells, which may account for the mechanism by which Adriamycin works in synergy with TRAIL (see figure). In addition to Adriamycin, we have also shown that several agents which effect an important regulatory protein in myeloma cells termed NFkb also increased the sensitivity of myeloma cells, including TRAIL resistant myeloma cells, to TRAIL treatment. One of these drugs, known as PS-341 is currently in clinical trials at our Institution.
The above preclinical studies suggest that TRAIL can overcome classical drug resistance, and that certain agents when used in combination with TRAIL may reverse resistance to TRAIL. These studies therefore provide the basis for clinical trials of TRAIL-based treatment regimens to improve outcome in myeloma patients. Phase I clinical studies with TRAIL are anticipated in mid 2001.
Note: These studies at Harvard Medical School and Dana Farber Cancer Institute were supported in part by a Brian D. Novis Fellowship Grant
from the IMF.