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 cancer drug may offer broad potential in the treatment of solid tumors

TGen Clinical Research Services (TCRS) is testing a new drug that may offer broad potential to treat solid tumors. Clinical trials of the drug TH-302, an anticancer agent in clinical development by Threshold Pharmaceuticals (1300 Seaport Blvd, Suite 500, Redwood City, CA 94063), are being conducted at the Mayo Clinic in Arizona by TGen Clinical Research Services, a partnership of Translational Genomics Research Institute (TGen) and Scottsdale Healthcare Corp.

Dr. Glen Weiss, Director of Thoracic Oncology at TGen Clinical Research Services TCRS at Scottsdale Healthcare, said the new drug appears promising and may be more effective and less toxic to healthy tissues than conventional drugs.

‘TH-302 is a new, novel, small molecule that is activated under a metabolic condition characteristic of cancer cells — hypoxia. The drug candidate may provide an opportunity to treat slowly dividing tumor cells within hypoxic regions that generally evade traditional chemotherapeutic agents and ultimately contribute to relapse,’ Dr. Weiss explained.

Phase I and Phase I/II trials are underway to investigate the safety and activity of TH-302 in patients with advanced solid tumors. After evidence of tumor activity was observed in the Phase I trial in patients with advanced melanoma – both non-small cell lung cancer and small cell lung cancer – the study was expanded to further investigate TH-302 anti-tumor activity in these tumors. Both Phase I and I/II trials continue to enroll patients with other solid tumors. If successful, Phase II and III clinical trials will confirm the drug's effectiveness on solid tumors.

Tumor hypoxia
Hypoxia is a condition in which there is a decrease in the oxygen concentration in tissue. In cancer, as a tumor grows, it rapidly outgrows its blood supply, leaving portions of the tumor with regions where the oxygen concentration is significantly lower than in healthy tissues. This condition is called tumor hypoxia. Several studies have shown that higher levels of tumor hypoxia correlate with poor treatment outcomes for a variety of solid tumors. It is believed that hypoxia may severely limit the curability of tumors.

This lack of oxygen in cancer cells compared to normal cells is exploited by Threshold’s Hypoxia-Activated Prodrug (HAP) platform. In time, this breakthrough technology platform may provide an opportunity to treat slowly dividing tumor cells within hypoxic regions that generally evade traditional chemotherapeutic agents and ultimately contribute to relapse.

A New Class of Drug
TH-302 is converted selectively in the presence of hypoxia to the drug’s active form, bromo-isophosphoramide mustard, a potent DNA alkylator. TH-302 targets levels of hypoxia that are common in tumors but are rare in normal tissues – this is how selective targeting of the tumor occurs. After conversion to the active form of the drug, the more resistant hypoxic cells are exposed to high concentrations of released cytotoxic agent, which can also diffuse into the oxygenated regions of a tumor cell. The Phase I/II trials are investigating the safety and activity of TH-302 in combination with a number of conventional chemotherapies that are believed to be effective in the non-hypoxic regions of solid tumors.

The clinical trial at TCRS at Scottsdale Healthcare will investigate the safety and pharmacology of multiple doses of TH-302 in patients with late-stage cancer.

The initial phase I clinical trial of TH-302 started in July 2007. In July 2008, interim results were presented. This trial was designed with an initial accelerated titration design followed by a standard dose escalation schema. The trial completed the accelerated titration design component and has enrolled the eighth dosing cohort. The weekly dose had been escalated from the initial dose of 7.5 mg/m2 to 670 mg/m2. None of the 20 patients enrolled at the time of the presentation has experienced any dose limiting toxicities (DLTs). One patient with refractory small cell lung cancer metastatic to the liver had a partial response at their initial response assessment with a greater than 45% reduction in target lesion diameters. The patient, who had received two cycles of TH-302, was being followed by RECIST (Response Evaluation Criteria In Solid Tumors) criteria. Other anti-tumor activity observed include one patient with non-small cell lung cancer with tumor shrinkage lasting over 6 months.

In August 2008, an additional clinical trial of TH-302 was initiated. The design of this trial included three separate treatment arms that will each examine TH-302 in combination with either gemcitabine, docetaxel or pemetrexed.

Approximately 50 patients with advanced solid tumors are planned to enroll in the Phase I/II, open-label, dose-escalation portion of the clinical trial. Up to six patients per dose level will participate in the dose escalation phase of the trial. Once the maximum tolerated dose (MTD) has been reached, the Phase II portion of the trial will enroll an additional 12 patients at the MTD within each treatment arm including gemcitabine in advanced pancreatic cancer patients, docetaxel in patients with castrate-resistant prostate cancer (CRPC) and pemetrexed in patients with non-small cell lung cancer.

Researchers expect that within the next several years a number of development candidates will arise from the hypoxia-activate prodrug platform.

For more information:

• Curd J, Sun J, Liu Q, et al, Targeting Tumor Hypoxia with TH-302 and Complementary Chemotherapy; 2nd American Association for Cancer Research (AACR) Conference on Translational Medicine, July 20-23, 2008; Monterey, CA. Drug Development/New Technologies: Poster Presentations - Proffered Abstracts, Abstract A5.
• Duan JX, Jiao H, Kaizerman J, et al. Potent and Highly Selective Hypoxia-Activated Achiral Phosphoramidate Mustards as Anticancer Drugs. Journal of Medicinal Chemistry, 51: 2412-2420, 2008.
• Hart C, Meng F, Banica M, et al., In vitro activity profile of the novel hypoxia-activated cytotoxic prodrug, TH-302. 99th American Association for Cancer Research (AACR) Annual Meeting, April 12-16, 2008; San Diego, CA, mTOR/Akt/PI3K Inhibitors and Vascular/Hypoxia Targeting Agents: Poster Presentations - Proffered Abstracts; Abstract 1441
• Jung D, Lin L, Plasma pharmacokinetics, oral bioavailability, and interspecies scaling of the hypoxically activated prodrug, TH-302, in mice, rats, dogs and monkeys. 99th American Association for Cancer Research (AACR) Annual Meeting- April 12-16, 2008; San Diego, CA, mTOR/Akt/PI3K Inhibitors and Vascular/Hypoxia Targeting Agents: Poster Presentations - Proffered Abstracts; Abstract #1447
• Hart C, et al., Discovery of TH-302: an achiral hypoxia-activated cytotoxic prodrug, American Society of Clinical Oncology (ASCO) Annual Meeting, June 2007.
• Wang J. Liu Q, Rosario G, et al., In vivo anti-cancer activity of a hypoxia activated prodrug, TH-302. American Association for Cancer Research (AACR) 98th AACR Annual Meeting, April 2007, 14-18, 2007; Los Angeles, CA. Meeting Abstracts, Apr 2007; 2007: 3988. Abstract # 3988.
• Ammons W, Wang J, Ma H, et al. Anti-tumor activity of a hypoxia activated prodrug, TH-302, in pancreatic and prostate orthotopic models of cancer. American Association for Cancer Research (AACR) 98th AACR Annual Meeting, April 14-18, 2007; Los Angeles, CA. Meeting Abstracts, Apr 2007; 2007: 3985. Abstract #3985

Note:

• The new version of RECIST (version 1.1) has been presented at the 20th EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics in Geneva, Switzerland (21-24 October 2008) and will be published in a special edition of the European Journal of Cancer in the first quarter of 2009.