ABSTRACT
Historically, metastatic melanoma has had extremely poor survival outcomes. The outlook, however, is rapidly changing as new molecularly targeted therapies have vastly improved patient outcomes. One such therapy is the potent mitogen-activated protein kinase kinase (MEK) 1/2 inhibitor cobimetinib. Recently, cobimetinib was approved for the treatment of metastatic or unresectable melanoma with serine/threonine-protein kinase B-raf (BRAF) V600E or V600K mutations when used in combination with the BRAF inhibitor vemurafenib. Currently, multiple clinical trials are investigating this drug combination for the treatment of various cancer types (e.g., breast, melanoma, colorectal). In the phase III coBRIM trial, this combination therapy showed improved melanoma response rates and patient progression-free survival when compared to vemurafenib alone. Additionally, toxicities were generally found to be manageable with dose modification or interruption. However, tumor response to BRAF/MEK inhibition, though rapid, is often short-lived as tumors develop resistance to this combination therapy. Therefore, new trials are beginning to investigate the addition of a third targeted agent or immunotherapy in order to increase the durability of treatment response. These trials are already showing promising preliminary results.
Subject(s)
Azetidines/therapeutic use , MAP Kinase Kinase 1/antagonists & inhibitors , MAP Kinase Kinase 2/antagonists & inhibitors , Melanoma/drug therapy , Mutation , Piperidines/therapeutic use , Proto-Oncogene Proteins B-raf/genetics , Azetidines/adverse effects , Azetidines/pharmacology , Clinical Trials as Topic , Drug Interactions , Humans , Melanoma/genetics , Piperidines/adverse effects , Piperidines/pharmacologyABSTRACT
The limitations of cancer cell lines have led to the development of direct patient-derived xenograft models. However, the interplay between the implanted human cancer cells and recruited mouse stromal and immune cells alters the tumor microenvironment and limits the value of these models. To overcome these constraints, we have developed a technique to expand human hematopoietic stem and progenitor cells (HSPCs) and use them to reconstitute the radiation-depleted bone marrow of a NOD/SCID/IL2rg(-/-) (NSG) mouse on which a patient's tumor is then transplanted (XactMice). The human HSPCs produce immune cells that home into the tumor and help replicate its natural microenvironment. Despite previous passage on nude mice, the expression of epithelial, stromal and immune genes in XactMice tumors aligns more closely to that of the patient tumor than to those grown in non-humanized mice-an effect partially facilitated by human cytokines expressed by both the HSPC progeny and the tumor cells. The human immune and stromal cells produced in the XactMice can help recapitulate the microenvironment of an implanted xenograft, reverse the initial genetic drift seen after passage on non-humanized mice and provide a more accurate tumor model to guide patient treatment.
