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).

Pemetrexed First Agent Approved in Europe as Maintenance Therapy for Advanced, Nonsquamous Non-Small Cell Lung Cancer

The European Medicines Agency’s (EMEA) Committee for Medicinal Products for Human Use (CHMP) has granted approval for the use of pemetrexed for injection (Alimta ®, Eli Lilly and Company) as monotherapy for maintenance treatment of patients with other than predominantly squamous cell histology in locally-advanced or metastatic non-small cell lung cancer (NSCLC), whose disease has not progressed immediately following platinum-based chemotherapy. This approval is based on data that showed pemetrexed improved overall survival in other than predominantly squamous NSCLC patients in the maintenance setting.

Globally, lung cancer is the most common form of cancer and the biggest killer, causing 1.3 million cancer deaths annually. This is more than breast, colon and prostate cancer taken together. About 85 - 90 percent of all lung cancers are non-small cell lung cancer (NSCLC). Survival rates are very poor.

Major disease forms
Non-small cell lung cancer (NSCLC) is defined as a group of histologies, that is, tumor types differentiated by cellular structure. The most predominant is squamous cell carcinoma (also known as epidermoid carcinoma) which accounts for 30 - 40% of all NSCLC cases. Formed from round cells that replace damaged cells along the epithelium of the main, lobar or segmental bronchi, this disease is a relatively slow growing carcinoma with a relatively good prognosis. Recurrence rates for resected squamous cell carcinoma are relatively low compared top other types of NSCLC, with distant metastases less common given the same treatment at the same stage.

Also referred to as nonsquamous histology, adenocarcinoma, which account for more than half of all NSCLC diagnoses, usually arises from mucus-producing cells of the lung. Aproximately two-thirds of adenocarcinomas develop in the outer regions of the lung, while the remaining one-third develop centrally. The majority of adenocarcinomas are asymptomatic until they have progressed to an advanced stage. As a consequence, the prognosis is generally worse compared to that of squamous cell carcinoma. On the other hand, once diagnosed, adenocarcinomas generally respond better to treatment than other NSCLC histologies.

Squamous cell carcinoma tends to metastasize in the bone, adrenal glands, liver, small intestines and brain. Because this disease is almost always caused by smoking, occurrence has decreased over the past 30 - 35 years.

Other types of NSCLC include bronchoalveolar carcinoma (BAC), a subclassification of adenocarcinoma with distinct clinical and pathologic properties and large cell carcinoma.

The majority of patients with NSCLC eventually develop metastatic disease or disease that is not a candidate for surgical interventions. this makes them potential candidates for systemic therapies. However, the decision on whether a patient receives therapy, greatly depends upon a number of factors, including the disease stage. In general, the more advanced the disease is, the more likely that a physician will prescribe a drug therapy.

Staging of Lung Cancer
Lung Cancer is often classified according to the American Joint Commitee on Cancer (AJCC) TNM staging system, and has five-tier staging, starting at 0 and rising to the severity of stage IV.

The primary T1 tumor, generally smaller than 3 centimeter, is usually easy to define on computed tomography (CT) and fluorodeoxyglucose positron emission tomography (FDG-PET).

TNM stage T3 tumors include tumors of any size with direct extension into the chest wall, diaphragm, mediastinal pleura or pericardium. Stage T4 tumors invade the mediastinum, great vessels, trachea, oesophagus and vertebral bodies.

Lung cancer in metastatic stage becomes aggressive. In this stage a therapy to shrink tumour size, stabilize the disease and relieve debilitating symptoms, with minimal toxic effects of the drug is required. Pemetrexed is the most promising molecule in that aspect. The drug provides better survival, progression free time and response and has superior tolerability than other cytotoxic drugs used for the same condition.

Mechanism of action
Pemetrexed is a multitargeted antifolate currently approved for first-line treatment of advanced, other than predominantly squamous NSCLC in combination with a platinum-based chemotherapy, and as a single agent in the second-line setting for advanced, other than predominantly squamous NSCLC patients with recurrent disease. Pemetrexed is chemically similar to folic acid and is in the class ofchenotheray drugs called folate antimetabolites. It works by inhibiting three enzymes used in purine and pyrimidine synthesis—thymidylate synthase (TS), dihydrofolate reductase (DHFR), and glycinamide ribonucleotide formyl transferase (GARFT).

Improve Overall Survival in a Maintenance Setting
The concept of maintenance therapy represents a paradigm shift in the treatment of advanced, other than predominantly squamous NSCLC.

Traditionally, patients who respond to first-line chemotherapy are monitored until the disease recurs and are then treated with a second-line regimen. In maintenance therapy, rather than halting further treatment until disease progression, patients who respond to a first-line therapy are treated immediately with a maintenance regimen.

"The idea behind ALIMTA as maintenance therapy for nonsquamous, non-small cell lung cancer is to treat patients immediately following their initial course of therapy, in an effort to prolong survival," said Richard Gaynor, M.D., vice president, cancer research and global oncology platform leader at Lilly. "The study that led to this approval was the first that showed improved overall survival in the maintenance setting for NSCLC. This was also the third trial to show the benefit of tailoring ALIMTA treatment to the nonsquamous NSCLC patient population."

Overall survival data for pemetrexed as a maintenance therapy for NSCLC was presented on May 31, 2009, at the 45th Annual Meeting of the American Society of Clinical Oncology (ASCO) by Chandra P Belani M.D.

The trial compared efficacy with respect to overall survival of pemetrexed plus best supportive care versus placebo plus best supportive care in 663 patients with stage IIIB/IV NSCLC whose disease had not progressed after four cycles of platinum-based induction chemotherapy. Pemetrexed was not included among the induction regimens studied in the maintenance trial. The trial supported two previous studies looking at the use of histology to tailor treatment for patients with advanced, other than predominantly squamous NSCLC.

Patients in the trial were treated with pemetrexed (500 mg/m2 on day one of each 21-day cycle) plus best supportive care or placebo plus best supportive care. All patients were supplemented with vitamin B12, folic acid and dexamethasone.

Pemetrexed was initially approved by the FDA in 2004 for the treatment of mesothelioma, with subsequent approval for second-line treatment of NSCLC.

This latest approval for pemetrexed - the fourth in Europe - follows an initial positive opinion issued by the European Medicines Agency's (EMEA) Committee for Medicinal Products for Human Use (CHMP) on May 29, 2009, and the recent approval by the U.S. Food and Drug Administration (FDA) of pemetrexed for maintenance therapy in advanced, nonsquamous NSCLC patients whose disease has not progressed after four cycles of platinum-based first-line chemotherapy.

Apart from the existing approvals in the EU and U.S. for the use of pemetrexed in the treatment of patients with locally-advanced or metastatic other than predominantly squamous NSCLC, pemetrexed is also approved, in combination with cisplatin, in both the EU and U.S. for the treatment of chemotherapy naive patients with unresectable malignant pleural mesothelioma.

For more information:

• Official Lilly Physician Resource for pemetrexemed
• Commitee for Medicinal Products for Human Use Post-Authorisation Summary of Positive Opinion for Alimta (EMEA)
• American Cancer Society: Lung Cancer - Non-Small Cell
• C. P. Belani, T. Brodowicz, et al. Maintenance pemetrexed (Pem) plus best supportive care (BSC) versus placebo (Plac) plus BSC: A randomized phase III study in advanced non-small cell lung cancer (NSCLC). Abstract #CRA8000. 2009 American Society of Clinical Oncology (ASCO) Annual Meeting. J Clin Oncol 27:18s, 2009 (suppl; abstr CRA8000).
• C.P. Belani. Maintenance Pemetrexed Plus Best Supportive Care (BSC) Versus Placebo Plus BSC: A Phase III Study in NSCLC. ASCO 2009 Annual Meeting. Oral presentation (Oral Presentation Chair(s): Jyoti D. Patel, MD; Karen L. Reckamp, MD)
• National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines in Oncology (Version 2.2006). Non-Small Cell Lung Cancer.
• Staging of non-small cell lung cancer (NSCLC)
• About the TNM System (Blog)
• American Joint Committee on Cancer: PowerPoint Presentation; Staging Lung Cancer.
• Mayo Clinic: Lung Cancer
• Lung Cancer Alliance

Also read these PubMed abstracts:

• Rossi A, Ricciardi S, Maione P, de Marinis F, Gridelli C. Pemetrexed in the treatment of advanced non-squamous lung cancer. Lung Cancer. 2009 Jul 3. [Epub ahead of print]
• Bobin-Dubigeon C, Amiand MB, Herrenknecht C, Bard JM. Development and validation of an improved liquid chromatography-mass spectrometry method for the determination of pemetrexed in human plasma. J Chromatogr B Analyt Technol Biomed Life Sci. 2009 Jun 21. [Epub ahead of print].
• Belli C, Fennell D, Giovannini M, Gaudino G, Mutti L. Malignant pleural mesothelioma: current treatments and emerging drugs. E xpert Opin Emerg Drugs. 2009 Jun 24. [Epub ahead of print]
• Racanelli AC, Rothbart SB, Heyer CL, Moran RG. Therapeutics by cytotoxic metabolite accumulation: pemetrexed causes ZMP accumulation, AMPK activation, and mammalian target of rapamycin inhibition. Cancer Res. 2009 Jul 1;69(13):5467-74. Epub 2009 Jun 23.
• Vlastos F, Hillas G, Vidal P, Lacomme S, Galateau-Sallé F, et al. Survey and Biological Insights of Pemetrexed-Related Therapeutic Improvement in Mesothelioma: The Nancy Centre of Biological Resources' Mesothelioma Cohort. J Thorac Oncol. 2009 Jun 19. [Epub ahead of print]
• Comella P, Chiuri VE, De Cataldis G, Filippelli G, Maiorino L, et al. Gemcitabine combined with either pemetrexed or paclitaxel in the treatment of advanced non-small cell lung cancer A randomized phase II SICOG trial. Lung Cancer. 2009 Jun 20. [Epub ahead of print]
• Scagliotti GV, Ceppi P, Capelletto E, Novello S. Updated clinical information on multitargeted antifolates in lung cancer. Clin Lung Cancer. 2009 Mar;10 Suppl 1:S35-40. Review.

How to help your patients:

• Encourage your patients to have an open, honest talk with you. Tell them that they should feel free to ask any question that’s on their mind, no matter how small it might seem. Also, encourage your patients to talk to other healthcare professionals, including nurses, social workers, and other members of the healthcare team.

Patient resources:

• ASCO’s Guideline on Adjuvant Treatment for Lung Cancer

Images courtesy American Society of Clinical oncology (ASCO)