Anti-Nodal Antibodies May Help Combat Metastatic Melanoma

It may be possible to combat metastatic melanoma in a new way involving a growth factor protein called Nodal.  Combining it with some current therapies may help patients who have not responded to standard therapy, according a new study published in Molecular Cancer Research, March 12, 2015.

Currently, the standard of care for metastatic melanoma patients is dacarbazine (DTIC), which is associated with poor patient outcomes. However, it is now theorized that it may be possible to combine dacarbazine with anti-Nodal antibodies to improve outcomes.

The recent discovery of Nodal's re-expression in several aggressive and metastatic cancers has highlighted its critical role in self-renewal and maintenance of the stem cell-like characteristics of tumor cells such as melanoma. The laboratory of Mary Hendrix, PhD, professor in the Robert H. Lurie Comprehensive Cancer Center in Chicago, made the novel discovery that embryonic stem cells and metastatic melanoma cells share a similar repertoire of receptors known as type I serine/threonine kinase(s), but diverge in their type II receptor expression. Further testing indicated that metastatic melanoma cells and embryonic stem cells use different receptors for Nodal signal transduction.

In the current study, Dr. Hendrix in collaboration with other scientists found that standard treatments for metastatic melanoma are not effective against Nodal. The study also showed that combination therapies incorporating anti-Nodal antibodies with dacarbazine are a promising alternative. The group discovered that Nodal-expressing cells not only remained after the therapy, but their numbers actually increased. Dr. Hendrix said the residual populations of tumor cells that were largely unaffected by dacarbazine were Nodal positive.

Dr. Hendrix said using a lower concentration of the dacarbazine with a low concentration of an anti-Nodal antibody may induce cell death and decrease cell growth synergistically. Tumor cells are very dependent on this growth factor and when you take it away they should die. Dr. Hendrix also said Nodal is still a relatively new observation, but it represents a promising cancer stem cell target.

At any time, 20% to 30% of melanoma tumor cells express Nodal, according to the current study.  The researchers reported that melanoma tumor cells expressing Nodal can increase cell proliferation to nearby cells that don’t produce the growth factor. Dr. Hendrix’s team is now investigating whether other melanoma therapies on the market affect Nodal, and, if they don’t, to determine if the therapies work in conjunction with anti-Nodal antibodies in a similar manner to the dacarbazine study. Dr. Hendrix reported that initial experiments with an agent that inhibits BRAF (a mutation found in a portion of melanoma tumors) suggest that a combination approach with an anti-Nodal antibody may be advantageous.