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).

New studies answer key questions about the treatment of gastrointestinal cancers

Findings from a number of large clinical trials of new treatment regimens for gastrointestinal cancers were released today at the 45th Annual Meeting of the American Society of Clinical Oncology (ASCO), being held in Orlando, May 29 - June 2, 2009 and will be highlighted in Onco’Zine – The international Cancer Blog.

“The studies presented today answer many important questions about the best care for people with gastrointestinal cancers,” said Nicholas Petrelli, MD, medical director of the Helen F. Graham Cancer Center in Wilmington, Delaware. “These large, conclusive trials tell us what works, and importantly, tell us what doesn’t work. Some settle long-time debates in the field, others demonstrate that the current standard of care is actually superior to experimental treatments, and others will allow patients to avoid unnecessary side effects or surgery.”

The results presented include:

• First-ever data on bevacizumab as adjuvant therapy finds no benefit in colon cancer: A phase III trial finds that adding the targeted therapy bevacizumab (Avastin, Roche), to standard adjuvant chemotherapy did not improve disease free survival for patients with locally advanced colon cancer.
• Surgery unnecessary for majority of patients with advanced colorectal cancer: Most patients with metastatic colorectal cancer can safely avoid surgery on their primary tumors.
• A trial compares common adjuvant treatments for pancreatic cancer: A phase III trial comparing the adjuvant treatments most commonly used for pancreatic cancer in the United States and Europe, gemcitabine (Gemzar, Eli Lilly and Company) and 5-FU/FA, respectively, found that there is no difference in survival between the two regimens, though gemcitabine was associated with fewer side effects.
• The largest study to date on anal cancer supports the current standard: A phase III study finds that the current standard of care for anal cancer should not be changed, and that ongoing maintenance therapy after initial treatment is not effective.
• Oxaliplatin does not improve outcomes for rectal cancer: Adding oxaliplatin (Eloxatin, Sanofi-Aventis) to standard treatment in patients with locally advanced rectal cancer does not improve tumor response. However, a preliminary analysis seems to suggests that the treatment may reduce distant metastases.

For more information:

• American Society of Clinical Oncology
• 2009 ASCO annual meeting abstracts

Reference:

• Medical-Oncology (at Boomja.com)

Zoledronic Acid May Have Anti-Tumor Properties

Early evaluations of the bisphosphonate zoledronic acid (Zometa® , Novartis Oncology) suggest a possible direct anti-tumor effect when combined with neoadjuvant chemotherapy in breast cancer treatment, according to data presented to scientists and other medical professionals gathered at the Henry B. Gonzales Convention Center in San Antonio to hear and present the latest scientific findings in breast cancer research during the CTRC-AACR San Antonio Breast Cancer Symposium (December 10-14, 2008 ).

There is substantial in vitro evidence that zoledronic acid has direct antitumour effects and synergy with chemotherapy agents. Bisphosphonates may therefore be an adjuvant therapeutic strategy of potential importance.

‘Zoledronic acid is primarily targeted to bone and metastasis within the bone marrow microenvironment, but it may also be enhancing the response in the primary breast tumor,’ explained Robert Coleman, M.D., FRCP, professor of medical oncology at the University of Sheffield in the United Kingdom.

Coleman is the lead researcher on the AZURE (Adjuvant Zoledronic Acid to Reduce Recurrence) trial, a prospective, randomised, open label, parallel group trial designed to to evaluate the effect of zoledronic acid on breast cancer. ‘Although the larger AZURE trial is still being evaluated, if the findings in this smaller study are confirmed, the effect could be practice changing,' Coleman said.

The AZURE trial opened to recruitment in September 2003. Patients were recruited from 176 centres worldwide, completing accrual in January 2006, 8 months ahead of schedule, and enrolled 3,360 women with stage II/III breast cancer. The trial was set up to determine whether adjuvant treatment with 4 mg zoledronic acid in addition to adjuvant or neoadjuvant chemotherapy would improve the disease-free and bone metastasis-free survival of women with breast cancer at high risk of relapse.

Analysis of the characteristics of the study population shows that both groups are well
matched across all criteria. 51% of patients have T2 tumour at presentation, with 76.6% being ER positive. 60.6% and 33.2% had 1-3 and ≥4 axillary nodes involved respectively and 6.4% were treated in the neoadjuvant setting. Anthracyclines were administered to 92.6% and 22.7% received taxanes, in large part due to accrual into the TANGO trial concurrent with AZURE. Only 4.6% received endocrine therapy alone. Almost half of the patients (44.6%) were premenopausal at randomisation.

Coleman and colleagues performed a retrospective pathology analysis on 205 patients who received neoadjuvant chemotherapy to determine zoledronic acid’s impact on the primary tumor. Zoledronic acid appeared to reduce tumor size from 30 mm in the chemotherapy alone group to 20.5 mm in the combination group.

After adjusting for variables like estrogen receptor status and treatment duration, the difference remained at 42.4 mm in the chemotherapy group and 28.2 mm in the combination group. The pathological complete response rate was 5.8 percent in the chemotherapy arm and 10.9 percent in the zoledronic acid group.

The number of patients requiring mastectomy was 77.9 percent in the chemotherapy group and 65.3 percent in the combination group. ‘Zoledronic acid is currently approved for the treatment of bone metastasis and osteoporosis. If the AZURE trial remains positive, then we’ll file for an additional indication,’ Coleman said.

For more information, read:

• Winter MC, Thorpe HC, Burkinshaw R, Beevers SJ, Coleman RE. The addition of zoledronic acid to neoadjuvant chemotherapy may influence pathological response exploratory evidence for direct anti-tumor activity in breast cancer. Abstract 5101. Poster Session V: Treatment: Neoadjuvant Therapy. San Antonio Breast Cancer Symposium.

Also read:

• Click here for full prescribing information.
• The Institute of Cancer Research

Also read PubMed Abstracts:

• Lyseng-Williamson KA. Zoledronic Acid: a review of its use in breast cancer. Drugs. 2008;68(18):2661-82
• Brufsky A. Management of cancer-treatment-induced bone loss in postmenopausal women undergoing adjuvant breast cancer therapy: a Z-FAST update. Semin Oncol. 2006 Apr;33(2 Suppl 7):S13-7.

Preliminary Study Results Demonstrate that Zoledronic Acid May Have Anti-Tumor Properties

Early evaluations of zoledronic acid, a bisphosphonate used for the treatment of bone metastases in advanced breast cancer, suggest a possible direct anti-tumor effect when combined with neoadjuvant chemotherapy in breast cancer treatment, according to data presented at the CTRC-AACR San Antonio Breast Cancer Symposium. Bisphosphonates may therefore offer an (neo)adjuvant therapeutic strategy of potential importance.

“Zoledronic acid is primarily targeted to bone and metastasis within the bone marrow microenvironment, but it may also be enhancing the response in the primary breast tumor,” said Robert Coleman, M.D., FRCP, professor of medical oncology at the University of Sheffield in the United Kingdom. Coleman is the lead researcher on the AZURE (Adjuvant Zoledronic Acid to Reduce Recurrence) trial, which is evaluating the effect of zoledronic acid on breast cancer.

Although the larger AZURE trial is still being evaluated, if the findings in this smaller study are confirmed, the effect could be 'practice changing,' Coleman said. The AZURE trial, a prospective, randomized, open label, clinical trial , enrolled 3,360 women with stage II/III breast cancer to determine whether treatment with zoledronic acid in addition to adjuvant or neoadjuvant chemotherapy would improve disease outcomes. Coleman and colleagues performed a retrospective pathology analysis on 205 patients who received neoadjuvant chemotherapy to determine zoledronic acid’s impact on the primary tumor. Zoledronic acid appeared to reduce tumor size from 30 mm in the chemotherapy alone group to 20.5 mm in the combination group. After adjusting for variables like estrogen receptor status and treatment duration, the difference remained at 42.4 mm in the chemotherapy group and 28.2 mm in the combination group. The pathological complete response rate was 5.8% in the chemotherapy arm and 10.9% in the zoledronic acid group.

The number of patients requiring mastectomy was 77.9% in the chemotherapy group and 65.3% in the combination group. “Zoledronic acid is currently approved for the treatment of bone metastasis and osteoporosis. If the AZURE trial remains positive, then we’ll file for an additional indication,” said Coleman.

For more information

• Winter MC, Thorpe HC, Burkinshaw R, Beevers SJ, Coleman RE, The addition of zoledronic acid to neoadjuvant chemotherapy may influence pathological response exploratory evidence for direct anti-tumor activity in breast cancer. Abstract 5101; SABCS, December 10-14, 2008.