Cancer Treatment

Decitabine and epigenetic therapy for solid cancers

Lay search: Decitabine is being studies for :epigenetic" therapy of solid cacners.

Genes involved in all aspects of tumor development and growth can become aberrantly methylated in tumor cells, including genes involved in apoptosis and cell cycle regulation. Decitabine, 2´-deoxy-5-azacytidine, can inhibit DNA methyltransferases and reverse epigenetic silencing of aberrantly methylated genes. Nucleoside DNA methyltransferase inhibitors, such as decitabine, have been reported to have antitumor activity, especially against hematologic malignancies. Such demethylating agents have been proposed to reactivate tumor suppressor genes aberrantly methylated in tumor cells, leading to inhibition of tumor growth.

Currenlty Decitabine is FDA approved for myedlodysplaisa. Because of the aforementioned emchanism of action, there is interest in studying it in colorectal and oterh solid cancers. Decitabine has been studied in several phase II trials for solid tumours as well as in different types of leukaemia. The drug has been shown to have very limited efficacy against solid tumours. However, decitabine exhibits higher activity for the treatment of haematological malignancies.

Robert Brown, Jane A Plumb Demethylation of DNA by decitabine in cancer chemotherapyExpert Review of Anticancer Therapy August 2004, Vol. 4, No. 4, Pages 501-510

Saba H, Rosenfeld C, Issa JP, et al. First Report of the Phase III North American Trial of Decitabine in Advanced Myelodysplastic Syndrome. American Society of Hematology Meeting. San Diego, Calif. 2004. Abstract #64.

Kantarjian H, O'Brien S, Giles F, et al.Decitabine Low-Dose Schedule (100 mg/m2/Course) in Myelodysplastic Syndrome (MDS). Comparison of 3 Different Dose Schedules.American Society of Hematology Meeting. Atlanta, Georgia. 2005. Abstract #2522.

http://jco.ascopubs.org/cgi/reprint/JCO.2004.01.947v1.pdf

Adis Decitabine: 2'-Deoxy-5-azacytidine, Aza dC, DAC, Dezocitidine, NSC 127716. R&D Profile Drugs in R & D. 4(6):352-358, 2003.

Jean-Pierre J. Issa DNA Methylation as a Therapeutic Target in Cancer Clinical Cancer Research 13, 1634-1637, March 15, 2007.

Cryoablation of kidney cancer

Standard approach to kidney cancers is surgical resection, usually a complete nephrectomy, althoguh partial nephrectomies are sometimes done when sparing renal function is imperative. Small renal masses have recently been treated by cryoablation (freezing to at least -19.4 °C using liquid nitrogen or argon). Subsequent MRI or CT scans are used to evaluate the ablation, with diminution of the tumor in the cryolesion and lack of contrast enhancement considered a favorable result, and increase of the tumor in the cryolesion or interval growth considered signs of inadequate treatment. A percutaneous biopsy, a standard resection, or retreatment with cryoablation can then occur. The mechanism leading to tumor destruction is uncertain and may be a combination of direct cytotoxicity and damage to vascular elements leading to ischemic necrosis. The cryoablation studies carried out to date fail to convince that a potentially malignant renal mass has been eradicated. The uncertain biopsy data before and after ablation, short follow-up, and requirements for lengthy general anesthesia and frequently for laparoscopic surgical intervention, weaken the argument for renal cryoablation as a paradigm shift.

Kaouk JH, Aron M, Rewcastle JC, Gill IS. Cryotherapy: clinical end points and their experimental foundations. Urology 2006;68(1 suppl):38–44.[

Paul Russo Renal cryoablation: a new treatment in need of careful clinical investigation Nature Clinical Practice Oncology (2006) 3, 286-287

Bortezomib for renal cell cancer

Lay Summary: Velcade, a myeloma drug, has activity in kidney cancer

Few treatment options exist for the patient with metastatic RCC. The majority of patients with metastatic RCC will die from their disease within 12 to 16 months of diagnosis, despite treatment with standard immune modulation. New agents with novel mechanisms are urgently needed for this clinical situation. Laboratory and preclinical studies have identified the proteasome as a potential target in solid tumor therapy , and this unique mechanism suggested that PS-341 may be efficacious in patients with RCC refractory to other therapies. There was a small phase II trial of PS-341 in patients with metastatic RCC. This study was closed after a planned analysis revealed only one objective response.  These observations suggest that a subset of patients with RCC may be responsive to proteasome inhibition. Unfortunately, have been dissapointing with that study having  one response in 21 patients. In a similar study from the Memorial Sloan-Kettering Cancer Institute, four of 37 patients with metastatic RCC responded to PS-341. Of the 37 assessable patients, the best response was a partial response in four patients (11%; 95% CI, 3% to 25%) and stable disease in 14 patients (38%; 95% CI, 23% to 55%). The four patients with partial response experienced response durations of 8, 8+, 15+, and 20+ months.

Drucker BJ, Schwartz L, Bacik J, et al: Phase II trial of PS-341 shows response in patients with advanced renal cell carcinoma. Proc Am Soc Clin Oncol 22:386, 2003 (abstr 1550)

Nancy B. Davis, David A. Taber, Rafat H. Ansari, Christopher W. Ryan, Christopher George, Everett E. Vokes, Nicholas J. Vogelzang, Walter M. Stadler  Phase II Trial of PS-341 in Patients With Renal Cell Cancer: A University of Chicago Phase II Consortium Study Journal of Clinical Oncology, Vol 22, No 1 (January 1), 2004: pp. 115-119

G. Varuni Kondagunta, Beverly Drucker, Lawrence Schwartz, Jennifer Bacik, Stephanie Marion, Paul Russo, Madhu Mazumdar, Robert J. Motzer Phase II Trial of Bortezomib for Patients With Advanced Renal Cell Carcinoma Journal of Clinical Oncology, Vol 22, No 18 (September 15), 2004: pp. 3720-3725