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Physician researchers at the Johns Hopkins Kimmel Cancer Center are actively pursuing new therapies and combinations of therapies for men with all stages of prostate cancer. Studying genetics, biology/immunotherapy, radiation techniques and natural therapies, at any given time our team runs 20 to 25 clinical trials for patients across the continuum, including perioperative cancers and more advanced disease. Several therapies being evaluated today, including the prostate cancer vaccine GVAX and the blood vessel-blocking drug tasquinimod, were developed right here in our laboratories.
Following is a sampling of some of our ongoing work:
In the laboratory of pathologist Angelo DeMarzo, researchers are focusing on the molecular development of prostate cancer. Dr. DeMarzo and colleagues are interested in determining the cell type of origin and the molecular mechanisms involved in early formation of prostate cancers. They also perform translational research in which they interrogate biomarker expression in human prostate tissues to help pathologists make diagnoses, help predict patient outcomes, help determine whether a given pathway alteration is present, or help determine whether a drug has hit its target.
One area of interest lately has been the MYC (“mick”) oncogene, which works like a gas pedal, causing cancer cells to grow and proliferate as it ramps up. Researchers have detected MYC in prostate cancers from its precursor lesions to metastatic disease. A study by Dr. DeMarzo, researcher Cheryl Koh and colleagues, published in the April 2011 issue of the American Journal of Pathology, found for the first time that overexpression of MYC increases the number and size of nucleoles, structures composed of proteins and acids found within the center of cells. Increased size and number of nucleoles are some of the earliest signs of physical changes associated with the development of premalignant prostate intraepithelial (PIN) lesions and invasive cancers; scientists previously had not known the cause of these changes.
Nucleoles produce ribosomes, which are important for cellular growth and proliferation. Additional studies could help better define the development of prostate cancers, which could lead the way to additional preventive treatments.
In basic science research, Dr. DeMarzo’s team has created mice that overexpress MYC in the prostate. Working with researchers at the University of Maryland, Dr. DeMarzo and colleagues have mixed the mice overexpressing MYC with mice missing the P10 tumor suppressor gene. The resulting mice have an explosion of cancers that metastasize to other organs. By studying these models, researchers hope to understand the mechnanisms behind how cancer cells break free of the original tumors and metastasize, and test new drug compounds.
Michael Carducci, Mario Eisenberger, Emmanuel Antonarakis, Charles Drake, and other investigators have been directing new combined immunotherapy studies in men with prostate and related cancers. Here is a description of a few of the studies. To find out more about these and other studies you may qualify for, speak with your physician or visit Kimmel's Clinical Trials page.
One area of study is a molecule on immune system T cells called PD-1 (programmed death-1), which, when activated by cancers, works like a brake and slows T cells’ ability to kill cancer cells. A study published by researchers at Johns Hopkins and other institutions in the July 1, 2010, issue of the Journal of Clinical Oncology showed that an antibody against PD-1 called MDX1106, infused in 39 patients with metastatic prostate cancer, kidney cancer, melanoma, non-small-cell lung cancer and colorectal cancer was well tolerated and in some patients helped T cells re-gain function and start destroying cancer cells. The antibody had lasting effects in a few patients, including one man with kidney cancer who received three doses of the antibody and was still alive three years later.
Additional studies of the antibody in patients with advanced kidney cancers will to try to determine why some patients respond to the drug and some do not, and how the medication works.
In patients with high-risk prostate cancers, a research team led by Drs. Drake and Antonarakis, will compare the effects of the PD-1 blockade drug alone or when given with the prostate cancer vaccine GVAX. They think patients will have a better immune response with the combined therapy.
Immunotherapy and Surgery
Drs. Drake and Antonarakis are conducting a pilot study to assess the antitumor immune effects of the prostate cancer GVAX given alone versus with a low dose of the drug cyclophosphamide in men with localized prostate cancer. These treatments also will be administered three weeks prior to surgery to remove the prostate in men with intermediate- and high-risk disease. Researchers aim to determine the immune effects of GVAX, and whether cylophosphamide given a day before GVAX strengthens the immune infiltration in to the prostate.
Androgen ablation, a hormone therapy that removes or suppresses testosterone, can “wake up” the immune system; it has been shown to be helpful for many patients with prostate cancers. A trial led by Drs. Antonarakis and Drake, along with researchers at the Cleveland Clinic, will compare the effects of androgen ablation on the immune system when combined with the prostate cancer vaccine Provenge. The team also will look at the response of PSA. Half of patients in the trial will get the vaccine before androgen ablation, and half after.
Immunotherapy and PSA levels
Dr. Drake and colleagues at Johns Hopkins are participating in a trial run by the Eastern Cooperative Oncology Group (ECOG) to compare whether men with metastatic prostate cancers fare better and have lower PSA levels when they receive chemotherapy before the prostate cancer vaccine Prostvac or after. Immune therapies alone don’t necessarily drop men’s PSA levels or shrink tumors; one theory is that they set the body up so that chemotherapy works more effectively by killing more tumor cells and ratcheting up the body’s immune system, Dr. Drake says.
New Drug Studies
- Dr. Carducci is leading a study of the drug Disulfiram, which may benefit prostate cancer patients by restoring tumor suppressor genes, in men with recurrent prostate cancer.
- Drs. Carducci and Antonarakis are directing Hopkins’ participation in a multi-center study of Itraconazole, an anti-fungal medication, in patients with metastatic castration-resistant prostate cancer. Early results indicate the drug can prevent prostate cancer from worsening and delay the need for chemotherapy in men with advanced disease. Please read for more information.
- Dr. Carducci is chairing a national phase III study evaluating the combination of the chemotherapy drugs docetaxel and prednisone with bevacizumab (a drug that blocks the growth of new blood vessels), versus just docetaxel and prednisone, in men with prostate cancer that did not respond to hormone therapy.
- Dr. Carducci is principal investigator of an international study evaluating the drug tasquinimod, which blocks the growth of new blood vessels, in men with metastatic castrate-resistant prostate cancer. A phase II study conducted at Johns Hopkins and other centers across the country showed the drug significantly slowed progression and improved progression-free survival in this population.
- Dr. Carducci is leading Hopkins’ participation in a multi-center study of the drug KX2-391, an inhibitor of Src kinase (a key regulator of tumor growth, blood vessel development and metastasis), in men with bone-metastatic castrate-resistant prostate cancer.
Alternative Medicine/Natural Product Therapies
Dr. Carducci is leading several studies of natural products, including pomegranate extract, Muscadine grape skin extract and Chinese coix-seed oil in men who have been treated for prostate cancer but still have rising PSA levels:
- In a phase II study, researchers found that pomegranate extract capsules slowed PSA doubling time by more than six months in a group of men with rising PSA levels following treatment for prostate cancer, with no effects on testosterone.
- Extract taken from the skin of Muscadine grapes has been shown to inhibit cell growth in lab studies; in an ongoing phase II study, Dr. Carducci and colleagues are comparing the effects of two doses of extract capsules on PSA doubling time.
- Dr. Carducci and colleagues are participating in a multi-center trial comparing two doses of Kanglaite gelcaps. The gelcaps contain oil from the coix grass plant, which has been used for therapeutic purposes in China for thousands of years. Anecdotally, the gelcaps have been reported to decrease PSA among prostate cancer patients. The extract also has been demonstrated to inhibit prostate tumor growth in animal models
- Prostate Cancer Updates from AACR 2010: Obesity Near Prostate Cancer Surgery Doubles Risk of Recurrence, Biomarkers Predict Candidates for Prostate Cancer Treatment.