Molecularly Targeted Therapy and Immunotherapy: The Next Frontier in Metastatic Bladder Cancer

Arjun Vasant Balar, MD

Assistant Professor, Department of Medicine

Co-Leader, Genitourinary Cancers Program

Laura and Isaac Perlmutter Cancer Center

The last major breakthrough in treatment for metastatic bladder (urothelial) cancer occurred in the 1980s, when cisplatin-based therapies, specifically MVAC (methotrexate, vinblastine, doxorubicin, and cisplatin), became the new standard of care. A major step toward improved tolerability of cisplatin-based therapy came in the early 2000s with the advent of the modern regimen of gemcitabine and cisplatin. However, the number of individuals who respond to this type of chemotherapy and the average survival have not significantly changed. More effective and better tolerated treatments remain a critical need.

Recent efforts toward the comprehensive molecular characterization of muscle-invasive urothelial bladder cancer—notably, the recent publication by The Cancer Genome Atlas (TCGA) Research Network in the journal Nature (2014;507[7492]:315-322)—have provided a detailed landscape of the varied genetic alterations in muscle-invasive urothelial cancer, giving promise to future trials of targeted therapies that may be selectively used to treat a specific patient’s tumor. With novel molecular biology dramatically opening up the field, intensified research is pointing to the identification of genetic biomarkers and better tolerated and more effective molecularly targeted therapies.

Immunomodulatory agents are also a new and promising class of treatments that present newfound optimism for the treatment of bladder cancer. First tested in patients with advanced melanoma, this class of immune-targeted therapy—more specifically, “immune checkpoint inhibitors”—also has the potential to revolutionize the treatment of advanced non— small cell lung cancer and advanced renal cell cancer, and is now being tested in advanced bladder cancer.

Bladder cancer researchers at NYU Langone Medical Center and its Laura and Isaac Perlmutter Cancer Center are working to better understand the mechanisms underlying the anticancer effect of these therapies, with the intent to help design the optimal treatment strategy for an individual patient.

As molecularly targeted therapies and immunetargeted therapies move through clinical trials, we hope to make major strides in improving the lives of patients with this devastating disease.

Immune Checkpoint Inhibitors

In June, recruitment commenced at NYU Langone and several clinical centers across the country on a multicenter, phase II, single-arm study of the immune checkpoint inhibitor MPDL3280A for advanced bladder cancer. This promising agent is a monoclonal antibody that blocks PD-L1, which is commonly expressed on bladder cancer cells, from binding to one of its receptors, PD-1, which is expressed on specific anticancer T cells. When activated, the PD-1 receptor on T cells signals an “off-switch” or “checkpoint” for these T cells, preventing its anticancer effect and allowing the bladder cancer cells to grow and invade unchecked. By blocking this interaction, we hope to reactivate the body’s own immune system against bladder cancer.

A particular strength of NYU Langone’s Perlmutter Cancer Center is the research of our dedicated laboratory, led by Xue-Ru Wu, MD, professor of Urology and Pathology, in studying bladder cancer biology in a mouse model of bladder cancer with an intact immune system.

His work using transgenic mouse models of bladder cancer has led to seminal insights into the molecular biology of bladder cancer and now serves as a unique model in which to test and better understand immune checkpoint inhibitors.

Cell-Cycle Regulation and Bladder Cancer

A hallmark of cancer is loss of cell-cycle control, leading to unrestricted proliferation of cancer cells’ cyclin-dependent kinases (CDKs), which are enzymes that regulate the cell cycle and are over-activated in many cancers, resulting in rapid proliferation. Data from the recently published TCGA analysis of bladder cancer identified CDKs 4 and 6 as over-activated in a significant proportion of patients with bladder cancer. Specific CDKs are only active during certain parts of the cell cycle, making careful pinpointing of pharmacokinetics, dosing, and targeting of compounds essential. Agents that selectively block both CDKs, potentially arresting growth of a cancer cell before it can replicate its DNA, are actively under study. Two small molecule inhibitors of CDK 4 and 6 show tremendous promise: PD-0332991 and LEE001 will be investigated in advanced bladder cancer in the near future.

Regulating Gene Expression

Another exciting avenue of research involves genes that regulate chromatin, the complex of DNA and its supporting proteins, histones, and the native form of the genetic material within the cell’s nucleus.

The tightly compact interaction of histones with DNA serves to “silence” specific genes from being expressed, and chromatin remodeling genes alter or open this interaction to allow genes to be expressed.

Mutations in key regulators of chromatin remodeling, namely MLL2, ARID1A, and KDM6A, were discovered in nearly 90% of all bladder cancers analyzed by the TCGA. While research has not yet identified the optimal way to target these mutations, histone deacetylase (HDAC) inhibitors, DNA methyltransferase inhibitors, and bromodomain inhibitors may hold promise in the future.

Old Targets, Better Ammunition

Receptor tyrosine kinases (RTKs) expressed on the surface of cancer cells, and in the enzymes inside the cancer cell that are linked to specifc RTKs, are well known to be commonly mutated in a variety of cancers. These mutations typically lead to uncontrolled cell signaling, proliferation, and cancer-cell invasion. Once again, the TCGA analysis identified a number of previously known mutations and a few novel mutations in specific components of these pathways, including ERBB2, FGFR3, and the PI3-kinase/AKT/mTOR pathway. A number of new compounds targeting these pathways, which are more potent and selective, are currently in development.

Combined with a better understanding of the molecular biology of bladder cancer, these new compounds provide hope for the identification of an effective treatment for specific subsets of bladder cancer patients.

Promise for the Future

While we are still in the early stages of understanding the therapeutically relevant molecular biology of bladder cancer, recent breakthroughs in molecular characterization efforts, such as the TCGA analysis, as well as in the arena of immunotherapy, provide great promise for the future of bladder cancer treatment. It is painstaking work that must be done carefully. We remain optimistic that further scientific study will lead to the development of better tolerated and more effective treatments and, in doing so, improve survival for patients with bladder cancer.