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Treatments on the Horizon

The last few years have seen a real surge in interest and financial support. With the creation of the grant-making Greenberg Bladder Cancer Institute and a renewed commitment to the disease among institutions around the world, we’re starting to see tangible progress.

Here’s a peek at some of the promising research — much of which is being done right here at the Greenberg Institute. There’s real hope that current research could positively impact bladder cancer patients in the years to come.

  • Novel immunotherapy approaches to nonmuscle-invasive and muscle-invasive bladder cancer – Trinity Bivalacqua, M.D., Ph.D., and Noah Hahn, M.D., form a truly unique urology-medical oncology partnership that is actively enrolling, treating and monitoring patients receiving treatment on innovative immunotherapy trials in nonmuscle-invasive and muscle-invasive bladder cancer. Bivalacqua and Hahn see patients jointly in the Johns Hopkins Outpatient Center urology clinic, with Bivalacqua overseeing the urologic aspects and Hahn overseeing the medical oncology management issues of their mutual patients.

    Examples of cutting-edge nonmuscle-invasive bladder cancer immunotherapy trials that they lead include an intravesical, virus-based vaccine approach and studies testing the effectiveness of systemically administered immune checkpoint inhibitors as monotherapy or in combination with BCG, radiation and other therapies. In muscle-invasive bladder cancer, Bivalacqua and Hahn are teaming up to perform the first randomized trial in the world examining the potential benefits of treating muscle-invasive bladder cancer patients who are not eligible for chemotherapy with the novel immune checkpoint inhibitor nivolumab (a PD-1 antibody) by itself or in combination with a second immunotherapy drug, known as urelumab (a 4-1BB antibody), aimed at stimulating the immune system. This study opened to enrollment in December 2016 and is being conducted only at Johns Hopkins. Learn about clinical trials.
  • Immunotherapy for improving bladder preservation outcomesHahn is working with leadership across the bladder cancer research community to develop a protocol for combining radiation with immunotherapy. There’s a lot of evidence that immune checkpoint inhibitors are effective in treating bladder cancer, so the hope is that this approach can be used to improve preservation outcomes for patients with muscle-invasive bladder cancer. Hahn aims to open a clinical trial in 2017.
  • Bladder preservation with neoadjuvant chemotherapy – Patients whose tumors contain specific DNA repair mutations may be treated with neoadjuvant chemotherapy alone. Greenberg Institute investigators are collaborating with other researchers to test this possibility in ongoing and planned clinical trials.
  • FGFR inhibitors – Activating mutations in FGFR3 are present in almost a fifth of advanced bladder cancers. Greenberg Institute investigators are involved in clinical trials to determine whether patients whose tumors contain these mutations can benefit from specific FGFR inhibitors.
  • Tissue engineering to improve neobladders – Most of the complications that come after radical cystectomy are from the GI reconstruction to either make a conduit for passage of urine or a neobladder for storage of urine, not from the surgical removal of the bladder. Urinary conduits have been used for 100 years, but because they’re made with the patient’s intestine, they can cause complications, including urinary tract infections, GI tract obstruction and chronic kidney disease.

    Bivalacqua, Nikolai Sopko, M.D., Ph.D., and Anirudha Singh, Ph.D., have developed an alternative to a urinary conduit that uses the patient’s autologous cells to seed a scaffold that will ultimately grow into a urinary reservoir for storage of urine. This novel technology is termed tissue engineering or regenerative medicine. Their lab is currently improving the durability of the neo-urinary conduit and ultimately neobladder for future use in bladder cancer patients.
  • Nanomedicine for drug delivery – Bivalacqua and colleagues Max Kates, M.D., and Laura Ensign-Hodges, Ph.D., received a grant from the Greenberg Bladder Cancer Institute to further develop a technology that uses nanoparticles to package immunotherapies and chemotherapies for more efficient delivery into the bladder. This will likely improve intravesical drug delivery to the bladder and help prevent recurrence and progression of bladder cancer in patients with nonmuscle-invasive bladder cancer. Read more about the grant.
  • Immunotherapy for metastatic bladder cancer – Intravesical immunotherapy has been used for several decades with a successful track record, but studies are showing promise that these drugs can also work on advanced and metastatic bladder cancer. Hahn is leading an international trial of the immune checkpoint inhibitor durvalumab (a PD-L1 antibody) in combination with several different targeted therapies that are chosen based the genetic mutations present in an individual patient’s tumor. Learn more.

  • Epigenetic therapy approaches to bladder cancer – Epigenetics refers to inheritable modifications of an individual’s DNA that are not the result of mutations in the DNA. These changes may lead to coiling or uncoiling of specific regions of DNA that are responsible for tumor suppressor, immune response and other key tumor control mechanisms. The laboratories of Bivalaqua and Hahn are actively investigating and collaborating to develop novel epigenetic therapy approaches to improve the outcomes of patients with bladder cancer of all stages.

  • Novel bladder cancer tumor models – With the promising clinical results seen with the use of immune checkpoint inhibitors targeting PD-1/PD-L1 mediated tumor growth, a critical need exists for improved bladder cancer models in animals with an intact immune system. Bivalacqua has developed a novel, toxin-induced bladder cancer model in immunocompetent laboratory rats that recapitulates the growth of bladder tumors from nonmuscle-invasive bladder cancer to muscle-invasive bladder cancer to metastatic stages. Within this rat bladder cancer model, his lab is investigating novel approaches to improve outcomes to BCG treatments and ways to improve delivery of intravesical treatments to tumor cells. Hahn has teamed up with Debbie Knapp, D.V.M., at the Purdue University College of Veterinary Medicine to establish naturally occurring bladder cancer in dogs as a clinically relevant immunocompetent model for bladder cancer comparative oncology research. Hahn and Knapp have conducted and published results of clinical trials and genetic sequencing investigations utilizing the canine bladder cancer model. Hahn’s lab is actively investigating areas of tumor biology that are shared between the human and canine species that can be exploited to accelerate drug development to the benefit of both species.

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