Researchers find Drug that Reverses Resistance to Chemotherapy in Pancreatic Cancer

Pancreatic adenocarcinoma is a common malignancy that remains refractory to many available therapies. For many years, 5-fluorouracil (5-FU) in combination with radiation therapy has been the only available treatment for patients with a resectable tumor. For patients whom the tumor had not metastasized but could not be surgically removed either, the combination of 5-FU and radiation therapy appeared to retard tumor growth and prolong survival.

Today, gemcitabine (Gemzar®, Eli Lilly and Company, USA) is the standard, first-line agent in advanced disease. The epidermal growth factor receptor (EGFR) is a commonly expressed target in pancreatic cancer that is involved in tumor proliferation, metastasis, and induction of angiogenesis. The addition of the EGFR inhibitor erlotinib to gemcitabine has recently been demonstrated to provide a small, yet statistically significant, survival benefit in advanced disease. Ongoing studies are comparing gemcitabine as a single therapy and in combination with of 5-FU. Researchers are also exploring the benefit of gemcitabine in combination with other chemotherapeutic agents such as cisplatin, docetaxol (Taxotere®, Sanofi-Aventis, France), or irinotecan (Camptosar®, Pfizer, USA).

Now, for the first time researchers have shown that by inhibiting the action of an enzyme called TAK-1, it is possible to make pancreatic cancer cells sensitive to chemotherapy, opening the way for the development of a new drug to treat the disease.

Dr Davide Melisi told Europe’s largest cancer congress, ECCO 15 – ESMO 34, the combined the 15th congress of the European CanCer Organisation and the 34th congress of the European Society for Medical Oncology, in Berlin, Germany, that resistance to chemotherapy was the greatest challenge to treating pancreatic cancer.

“Pancreatic cancer is an incurable malignancy, resistant to every anti-cancer treatment. Targeting TAK-1 could be a strategy to revert this resistance, increasing the efficacy of chemotherapy,” Melisi said, who until the start of September was a Fellow at the M.D. Anderson Center in Houston (Texas, USA); he has now moved to a staff position at the National Cancer Institute in Naples (Italy). “During the past few years we have been studying the role played by a cytokine or regulatory protein called Transforming Growth Factor beta (TGFbeta) in the development of pancreatic cancer. Recently we focused our attention on a unique enzyme activated by TGFbeta, TAK-1, as a mediator for this extreme drug resistance.”

Melisi and his colleagues investigated the expression of TAK-1 (TGFbeta-Activated Kinase-1) in pancreatic cell lines and developed a drug that was capable of inhibiting TAK-1. They tested the activity of the TAK-1 inhibitor on its own and in combination with the anti-cancer drugs gemcitabine, oxaliplatin and SN-38 (a metabolite of the anti-cancer drug irinotecan) in cell lines, and the activity of the TAK-1 inhibitor combined with gemcitabine against pancreatic cancer in mice.

“The use of this TAK-1 inhibitor increased the sensitivity of pancreatic cells to all three chemotherapeutic drugs. By combining it with classic anti-cancer drugs, we were able to use doses of drugs up to 70 times lower in comparison with the control to kill the same number of cancer cells. In mice, we were able to reduce significantly the tumour volume, to prolong the mice survival, and to reduce the toxicity by combining the TAK-1 inhibitor with very low doses of a classic chemotherapeutic drug, gemcitabine, that would have been ineffective otherwise,” noted Melisi.

The use of gemcitabine on its own against the cancer in mice was ineffective because of the drug resistant nature of the disease. However, once it was combined with the TAK-1 inhibitor, Dr Melisi and his colleagues saw a 78% reduction in tumour volumes. “The median average survival for the control, TAK-1 inhibitor, gemcitabine on its own, or TAK-1 inhibitor combined with gemcitabine was 68, 87, 82 and 122 days respectively,” he explained.

“This is the first time that TAK-1 has been indicated as a relevant target for the treatment of a solid tumor and that it is a valid approach to reverting the intrinsic drug resistance of pancreatic cancer. The TAK-1 inhibitor used in this study is an exciting drug that warrants further development for the treatment of pancreatic cancer. In the near future, we will study whether it is also able to make other chemotherapeutic agents, such as oxaliplatin, 5-FU or irinotecan, work against pancreatic cancer in mice."

“Our main goal is to translate this combination approach from the bench to the bedside, conducting a clinical trial that could demonstrate the safety of this TAK-1 inhibitor in combination with gemcitabine, and its efficacy, in pancreatic cancer patients,” Melisi told his audience.

For more information:

• Abstract no: 1002, Basic science/translational research session, Thursday 09.00 hrs CEST (Hall 14.2)

Also read these PubMed Abstracts:

• Ge C, Luo X, Chen X, Guo K. Enucleation of Pancreatic Cystadenomas. J Gastrointest Surg. 2009 Sep 25. [Epub ahead of print]
• Melisi D, Niu J, Chang Z, Xia Q, Peng B, et al. Secreted interleukin-1alpha induces a metastatic phenotype in pancreatic cancer by sustaining a constitutive activation of nuclear factor-kappaB. Mol Cancer Res. 2009 May;7(5):624-33. Epub 2009 May 12.
• Cotton RT, Li D, Scherer SE, Muzny DM, Hodges SE, et al. Single nucleotide polymorphism in RECQL and survival in resectable pancreatic adenocarcinoma. HPB (Oxford). 2009;11(5):435-44.
• Faller BA, Burtness B. Treatment of pancreatic cancer with epidermal growth factor receptor-targeted therapy. Biologics. 2009;3:419-28. Epub 2009 Sep 15.

Highlights of Prescribing Information:

• Gemcitabine (Gemzar®) hydrochloride for injection
• Docetaxel (Taxotere®) Injection Concentrate
• Irinotecan hydrochloride injection (Camptosar®)

For your patients:

• Onco'Zine - The International Cancer Network
• The national Pancreas Foundation: Frequently Asked Questions
• American Cancer Society: What is Pancreatic Cancer (Detailed guide)

Images courtesy American Society of Clinical oncology (ASCO).

Standard of Care for Anal Cancer Should Not Be Changed

Findings from the largest trial ever conducted for anal cancer have shown that the current standard of care, using a novel, continuous radiation therapy delivery program combined with 5-fluorouracil (5-FU) , (a drug commonly used to treat many types of cancer including, breast, head and neck, anal, stomach, colon and some skin cancers), and mitomycin-C (a chemotherapy drug mainly used to treat bladder and rectal cancers, but also sometimes pancreatic, lung and breast cancers), results in the best outcomes so far reported for patients with anal cancer, and that cisplatin chemotherapy (a drug approved to be used together with other drugs to treat many different cancers), is not superior to mitomycin-C.

The study, presented on Saturday, May 30, 2009 by Roger James, MD, Maidstone Hospital, Kent, UK, during the 45th Annual Meeting of the American Society of Clinical Oncology (ASCO) being held from May 27 – June 2, 2009 in Orlando, Florida, also showed no evidence of a benefit of adding maintenance chemotherapy to the standard of care.

Anal cancer is rare, with about 5,000 patients diagnosed in the United States each year. In the United Kingdom about 850 people are diagnosed with this disease each year. It is slightly more common in women than men, with rates increasing in women over the past 10 years.

Unlike colorectal cancer, the majority of patients with anal cancer do not need surgery, largely because the tumors are the squamous cell type, which are very responsive to chemotherapy and radiation. Cisplatin is commonly used for other squamous cell cancers, but it is less convenient to deliver and is known to have different toxicities from mitomycin-C, such as neurological and renal side effects and hearing loss.

The current study, called ACT II, conducted by the National Cancer Research Institute in the United Kingdom, and funded by Cancer Research UK, randomized 940 patients to receive radiation therapy given at the same time as 5-FU with either mitomycin-C or cisplatin. Patients were also randomized to receive follow-up maintenance therapy with cisplatin and 5-FU after chemoradiation or no maintenance therapy.

After a median follow-up of three years, the investigators found no significant difference in outcome in the two randomized comparisons:

• The complete response rate at 6 months (the number of patients who had all signs of their cancer disappear) was 94 percent in the mitomycin-C group compared with 95 percent in the cisplatin group.
• Recurrence-free survival at 3 years (the number of patients whose tumors did not return) was 75 percent both in patients who got maintenance therapy and in those who did not.
• Overall survival at 3 years was 85 percent in patients who received maintenance therapy and 84 percent in those who did not.

“These findings are good news in spite of the lack of evidence for an improvement in giving either cisplatin or maintenance therapy, since the standard chemoradiation schedule given in this trial was highly effective,” said Roger James, MD, FRCP, FRCR, a radiation oncologist from Maidstone Hospital, Kent, United Kingdom, and the study’s lead author. “Although this trial did not show an improvement from adding maintenance therapy, some form of additional treatment will be the subject of future studies, to determine whether some subset of patients might benefit from it.”

For more information:

• The National Cancer Research Institute (NCRI)
• Cancer Research UK
• Anal Cancer trials (UK)
• Glynne-Jones R, Mawdsley S, Anal Cancer: The End of the Road for Neoadjuvant Chemoradiotherapy? Journal of Clinical Oncology (JCO), Vol 26, No 22 (August 1), 2008: pp. 3669-3671

2009 ASCO Annual Meeting Abstracts:

• James R, Wan S, Glynne-Jones R, Sebag-Montefiore D, Kadalayil L, Northover J, Cunningham D, Meadows M, Ledermann J, National Cancer Research Institute (NCRI) ACT II Trial Management Group. A randomised trial of chemoradiation using mitomycin or cisplatin, with or without maintenance cisplatin/5FU in squamous cell carcinoma of the anus (ACT II) LBA4009

Illustration courtesy of the American Society of Clinical Oncology.