Melanoma differentiation associated gene-7/interleukin-24 (mda-7/IL-24): novel gene therapeutic for metastatic melanoma

Abstract

A potentially less toxic approach for cancer therapy comprises induction of tumor cells to lose growth potential irreversibly and terminally differentiate. Combining this scheme termed 'differentiation therapy of cancer' with subtraction hybridization to human melanoma cells resulted in the cloning of melanoma differentiation associated (mda) genes displaying elevated expression as a consequence of induction of terminal differentiation. One originally novel gene, mda-7, was found to display elevated expression in normal melanocytes and nevi with progressive loss of expression as a consequence of melanoma development and progression to metastasis. Based on structure, biochemical properties and chromosomal location, mda-7 has now been reclassified as interleukin (IL)-24, a member of the expanding IL-10 family of cytokines. In vitro cell culture and in vivo animal studies indicate that mda-7/IL-24 selectively induces programmed cell death (apoptosis) in multiple human cancers (including melanomas), without harming normal cells, and promotes profound anti-tumor activity in nude mice containing human tumor xenografts. Based on these remarkable properties, a Phase I clinical trial was conducted to test the safety of administration of mda-7/IL-24 by a replication incompetent adenovirus (Ad.mda-7; INGN 241) in patients with advanced solid cancers including melanoma. mda-7/IL-24 was found to be safe and to promote significant clinical activity, particularly in the context of patients with metastatic melanoma. These results provide an impetus for further clinical studies and document a central paradigm of cancer therapy, namely translation of basic science from the "bench to the bedside."

Figure 1

Strategy for identifying genes differentially expressed during induction of irreversible growth arrest and terminal differentiation in human melanoma cells. Subtraction hybridization was combined with a treatment protocol, IFN-β plus MEZ, that promotes terminal differentiation in metastatic HO-1 human melanoma cells. This approach, termed differentiation induction subtraction hybridization (DISH), has resulted in the cloning of melanoma differentiation associated (mda) genes involved in important physiological processes, including growth control, differentiation and apoptosis (mda-6/p21 and mda-7/IL-24), metastasis (mda-9/syntenin), cellular senescence (human polynucleotide phosphorylase) and innate immunity (mda-5). Experimental details of the subtraction hybridization and DISH approach can be found in Jiang and Fisher (1993) and Huang et al. (1999). (From Fisher et al., 2003).

Figure 2

A hypothetical model of the involvement of p38 MAPK pathway and the GADD family members of genes in mediating apoptosis in human melanoma cells by Ad.mda-7. Ad.p38DN, Ad delivered dominant-negative mutant of p38 MAPK; SB203580, pharmacological inhibitor of p38 MAPK; GADD, growth arrest and DNA damage inducible gene; AS.GADD, antisense of GADD gene. (From Sarkar et al., 2002).

Fig. 3

INGN 241 (Ad.mda-7) treatment of a melanoma metastasis in a right supraclavicular lymph node. (A) Pretreatment. (B) Inflammation by post-injection day 4. (C) Complete regression post-injection day 30. (From Cunningham et al., 2005).