Impact of Valproate on Angiogenesis and Histone Deacetylation in Bladder Cancer

Bladder cancer is the fourth most common cancer in the United States with over 60,000 new
cases each year. It can usually be treated initially by insertion of an endoscope into the
bladder and surgically removing the tumor, a procedure known as cystoscopy and
trans-urethral resection of bladder tumor (TURBT). For most patients this procedure will
successfully remove all of the detectable tumor. Unfortunately over 40% of all patients will
develop a cancer recurrence in less than two years and all patients remain at increased risk
of recurrence for the remainder of their lives. This risk requires life long monitoring and
this is best accomplished with regular cystoscopic examinations. The goal of this study is
to test whether the drug valproic acid can cause changes in bladder tumors that might
inhibit their growth. Patients with suspected bladder cancer will be invited to participate
in the study, if a tumor is observed during cystoscopy it will be sampled for research
purposes and then according to standards of care, the patient scheduled for TURBT under
general anesthesia. In the interval between discovery of a bladder tumor and resection,
usually two to four weeks, the patient will be given valproic acid to take orally. In
addition, tumors from patients with known or suspected bladder cancer referred for TURBT or
cystectomy will be sampled. The tumor pieces obtained before and after taking valproic acid
and from the referral patients not treated with valproic acid will be analyzed to see if the
drug has changed what genes are active. We have found that valproic acid causes bladder
cancer cells to make more of the protein, thrombospondin-1. This protein inhibits the growth
of new blood vessels and so increased thrombospondin-1 in bladder tumors should inhibit
their growth by decreasing the blood supply. Valproic acid may change thrombospondin-1
levels through inhibition of histone deacetylases. We will also assay HDAC activity in the
tumor specimens. If valproic acid alters thrombospondin-1 levels and HDAC activity in
bladder cancer patients further study to see if it can reduce growth will be justified.
Valproic acid is a drug approved for the treatment of seizure disorders that is generally
well tolerated with few side effects. It may prove useful in reducing bladder cancer
recurrence and progression.

Inclusion Criteria:

1. Patient over the age of 21

2. Bladder tumor suspected or confirmed

3. ECOG status 0 to 2

4. Premedication Lab values:

Absolute Neutrophil Count >750 cells/m3 AST/ALT less than 1.5xN Amylase less than 1.5xN
Platelet Count > 125,000 PT/PTT > 1.3xN Hemoglobin > 8gm/dL Creatinine less than 1.5xN

Exclusion Criteria:

1. Allergy to valproic acid

2. Concurrent chemotherapy

3. Pre-menopausal women

4. Active systemic infection (HepatitisB,C)

5. Coagulation disorders

6. Concurrent medication: Tolbutamide, Warfarin, Zidovudine, Benzodiazepine, Clonazepam,
Diazepam, Any anti-convulsant therapy

7. Seizure disorder

8. Dementia

9. History of Pancreatitis

10. HIV diagnosis/treatment

11. Liver disease/dysfunction