New Drug May Offer Hope for Adrenocortical Carcinoma Patients

TGen Clinical Research Services (TCRS) at Scottsdale Healthcare in Scottsdale, Arizona, recently announced the start of a clinical trial for a drug designed to combat adrenocortical carcinoma (ACC), a rare but deadly cancer that forms in the cortex (steroid hormone-producing tissue) of the adrenal glands, a small organ on top of each kidney that makes steroid hormones, adrenaline, and noradrenaline.

The adrenal glands are responsible for making several critical hormones, including cortisol, which the body needs in order to respond to stress and which helps to maintain normal blood sugar levels in children.

Adrenal carcinoma (ACC) affects 1 to 2 per million population annually and may be curable if treated at an early stage. Radical surgical excision is the treatment of choice for localized malignancies and remains the only method by which long-term disease-free survival may be achieved. Overall 5-year survival for tumors resected for cure is approximately 40%. Retrospective studies have identified two important prognostic factors: completeness of resection and stage of disease. The most common sites of metastases are the peritoneum, lung, liver, and bone.

Other than surgery, the only treatment for ACC is the exacting use of a compound called mitotane (Lysodren®, Bristol-Myers Squibb), a chemical relative of DDT, which the U.S. banned as an insecticide in 1972, systemic chemotherapy, or (for localized lesions) radiation therapy.

While use of mitotane in ACC patients reduces tumors, it also diminishes adrenal gland function, requiring patients to take hormone replacements for the rest of their lives. In addition, mitotane must be administered for at least three months in order to reach a therapeutic level. Even then, it has proved effective in about 22% of ACC cases. When given with other chemotherapy drugs, the effectiveness of mitotane may be improved, but patients often suffer debilitating side effects.
Clinicians at TGen Clinical Research Services (TCRS), a strategic alliance between the Translational Genomics Research Institute (TGen) and Scottsdale Healthcare, hope that a new compound, OSI-906, a small molecule IGF-1R inhibitor that blocks the chemical pathway that otherwise allows the ACC tumors to grow out of control.

The drug candidate is developed by OSI Pharmaceuticals Inc. of Melville, N.Y., and will stop ACC tumor growth — perhaps even promote tumor shrinkage — without the toxic side effects of current chemotherapies. The trial will focus on patients with inoperable tumors who have relapsed or failed to respond to conventional therapies.

IGF-1R inhibitor
OSI-906 is a potent, selective orally active inhibitor of the insulin-like growth factor-1 receptor (IGF-1R) which has been viewed as an important therapeutic target due to its involvement in the growth and proliferation in a variety of human cancers, including adrenocortical carcinoma (ACC), ovarian and non-small cell lung cancers.

The new drug candidate stimulates proliferation, enables onogenic transformation, and suppresses apoptosis. Inhibitors of IGF-1R are expected to have broad utility in oncology since the over-expression of IGF-1R and/or its ligands or the down-regulation of ligand binding proteins occurs in numerous human malignancies including lung, colon, breast, prostate, brain and skin cancers. In addition, signaling through the IGF system has been implicated in protecting tumor cells from apoptosis induced by anti-cancer treatments such as cytotoxic agents and EGFR inhibitors. Scientists therefore believe that OSI-906 may be useful both as a single agent and in combination with other targeted therapies such as erlotinib (Tarceva® marketed by Genentech Bioncology and OSI Pharmaceuticals).

Ongoing research
During the 2009 annual meeting of ASCO, the American Society of Clinical Oncology, a number of abstracts were published with IGF-1R inhibitors in a range of cancers, making a case for insulin growth factor receptor (IGF-1R) inhibitors as a potential target for cancer therapeutics. So far, the data presented at ASCO has been very preliminary and isolated responses were seen.
In addition to OSI (OSI-906), a number of pharmaceutical and research companies have active, ongoing research programs in the clinic. Many other companies are involved in preliminary research in different stages in different cancers (Exelixis/XL228, Amgen/AMG-479, Roche/R1507, Pfizer/CP-751,871/Figitumumab, BMS/BMS-754807, Merck/MK-0646, and Imclone/Lilly/IMC A12). Others companies, including Sanofi-Aventis, Novartis, Eisai, Biogen Idec, are interested to see how this new class pans out.

OSI-906 trial
A clinical trial of OSI-906 is expected to last several years and include 135 patients, with 30-40 enrolled at TCRS. As there is no standard therapy available, two-thirds of the patients will receive the drug OSI-906 while one-third receives a placebo. Sites elsewhere in the U.S., as well as in Europe and Australia, are expected to enroll patients over the coming months.

“The trial is major step toward helping patients with ACC, who often face radical surgery as part of their treatment,” said Dr. Michael J. Demeure, who will oversee the trial locally. Dr. Demeure is a TGen Senior Investigator and a Scottsdale Healthcare surgeon experienced in removing ACC tumors.

“It’s a big operation requiring a large incision because these tumors can be the size of a football. Unfortunately many patients’ tumors have spread so we can’t remove it all, so new treatments are needed.’’ Demeure explained. “This unique partnership between Scottsdale Healthcare and TGen allows us to bring the newest and most promising treatments to patients with cancer right here in Arizona.”

The TCRS clinic in the Virginia G. Piper Cancer Center at Scottsdale Healthcare Shea is the first site worldwide approved for these clinical trials.

"Being the first site in the world for clinical trials of this drug adds to the long list of ‘firsts’ for the Virginia G. Piper Cancer Center,” said Mark Slater, Ph.D., vice president of research. "Scottsdale Healthcare’s collaborations with world-class physicians and scientists are helping pave the way for exciting new cancer treatments to benefit patients with cancer everywhere.”

Although the disease is very rare, Demeure said that developing a new drugs against this orphan indication is worth the effort and expense. “Patients with rare tumors have unique challenges. Often it is difficult for them to find a doctor who even knows about their disease,” he said. “What we learn taking care of those patients with ACC could help us learn how to take care of others with rare tumors.’’

The clinical trial follows nearly 3 1/2 years of research at TGen, initiated through the efforts of patient advocate and ACC survivor, Mr. Troy Richards.

Richards, a Scottsdale resident, has battled ACC since 1999. To combat what little research he saw being done on the disease, he began the Advancing Treatments for Adrenocortical Carcinoma (ATAC) fund, which helped finance the ACC Research Program at TGen.

"The ACC project at TGen has finally given those of us with the disease hope for better treatments, and maybe one day a cure,” said Mr. Richards. “It is my hope that this program can serve as a model for other rare diseases, and that patients will realize they do have the power to make a difference.”

Dr. Kimberly Bussey, a TGen Associate Investigator and Lead Investigator for TGen’s Adrenocortical Carcinoma Research Program, said, “Troy brings a sense of urgency and a connection to the ACC patient community that made this trial possible. This is a huge accomplishment for the ACC Research Program at TGen and a great testament to what patient-advocated research can accomplish in a short period of time.”

“We are eagerly awaiting the opening of this study,” said Dr. Maqbool Halepota, an oncologist with the Palo Verde Hematology/Oncology group based at the Virginia G. Piper Cancer Center at Scottsdale Healthcare. “I firmly believe that targeted therapies are the future of cancer care, and our partnership with TCRS allows patients in the Phoenix area access to many innovative trials.”

For additional information:

• Scottsdale Clinical Research Institute
• Scottsdale Healthcare Foundation
• Virginia G. Piper Cancer Center
• TGen Clinical Research Services

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).

Cetuximab plus Chemotherapy may Reduce Advanced Lung Cancer Death Risk

Patients with advanced non-small cell lung cancer who are given cetuximab (Erbitux, Merck KgA), an immunoglobulin (Ig) G1 chimeric monoclonal antibody against the epidermal growth factor receptor, in addition to chemotherapy are 13% less likely to die than those who receive chemotherapy alone, regardless of which chemotherapy is used, new research finds. They also experience slower disease progression and an increased chance of tumor shrinkage.

While a large study last year found that patients lived five weeks longer when the targeted drug cetuximab was added to a particular chemotherapy combination, it has not been clear whether it matters which chemotherapy combination the drug is added to, how its addition affects disease progression and what the exact magnitude of the survival benefit is.

Researchers combined the data from four trials that investigated the addition of cetuximab to various different platinum-based chemotherapy combinations in first-line treatment of advanced non-small cell lung cancer. The findings of the meta-analysis, which included a total of 2,018 patients, were presented in Berlin on Tuesday at Europe’s largest cancer congress, ECCO 15 – ESMO 34 (the 15th congress of the European CanCer Organisation and the 34th congress of the European Society for Medical Oncology).

Meta-analyses, which integrate the results of several studies, are important for corroborating the findings of key studies and give a more accurate estimate of a drug’s true effects. “We found that patients who got cetuximab had a 13% lower chance of dying within the three years of follow-up compared with those who got chemotherapy alone,” said Professor Jean-Louis Pujol, chair of thoracic oncology at Montpelier Academic Hospital and professor of medicine at Montpelier University in France. “For lung cancer, considering that this disease is very resistant to treatment and that the prognosis is very poor, an improvement of that magnitude is meaningful. It’s about the same as what you get from giving chemotherapy after surgery and that’s accepted as standard treatment.”

The median survival, a more crude measure of the drug’s effect on death, was 9.4 months in the chemotherapy alone group and 10.3 months in the chemotherapy plus cetuximab group.

The meta-analysis also uncovered a 10% improvement in progression free survival, which measures the length of time a patient survives before the cancer gets worse. None of the individual studies were powerful enough to identify any effect on this outcome on their own, as it is difficult to observe this in lung cancer because the disease progresses so quickly.

The study also found that patients who received the addition of cetuximab were 48% more likely to experience tumour shrinkage.

“Fewer than 30% of patients with advanced non-small cell lung cancer respond to chemotherapy, so even though adding cetuximab increases the chance by another 48%, pushing the response rate up to about 45%, this shows than non-small lung cancer remains a disease that is very resistant to treatment,” Prof Pujol said.

The benefits for all these outcomes were seen across all subtypes of the disease. Lung cancer is particularly difficult to treat and is the leading cause of cancer death worldwide, killing an estimated 1.31 million people a year. Patients with advanced disease have few treatment options and about 70% of them die within one year of diagnosis. Fewer than two percent survive five years. Platinum-based chemotherapy is the standard treatment.

Non-small cell lung cancer (NSCLC) is the most common form of lung cancer and most patients have tumours that over-express the epidermal growth factor receptor (EGFR). Cetuximab belongs to a new class of anti-cancer drugs known as monoclonal antibodies and works by blocking the EGF receptor to interrupt uncontrolled cell division.

Studies of other EGFR blockers have not shown any benefit when they are combined with chemotherapy in first-line treatment of advanced non-small cell lung cancer, although they have been shown to help in second-line treatment. One explanation for why cetuximab has shown benefit in this case while the other drugs targeting the receptor haven’t could be because it blocks the receptor in a different location. The drug is currently used to treat metastatic colorectal cancer and head and neck cancer. Frequent side effects include an acne-like rash.

“We now have enough evidence to recommend cetuximab for patients with advanced non-small cell lung cancer and we have confirmation that it doesn’t matter what kind of chemotherapy it is used with,” Prof Pujol said. “What we now need to investigate is whether this drug could also help at early stages of the disease.”

The study was funded by a grant from Merck KGaA, which makes cetuximab.

For more information:

• Abstract no: 9009. Lung Cancer II session, Tuesday 09.00 hrs CEST (Hall 15.2)

Also read these Pubmed Abstracts:

• Reade CA, Ganti AK. EGFR targeted therapy in non-small cell lung cancer: potential role of cetuximab. Biologics. 2009;3:215-24. Epub 2009 Jul 13
• Belani CP, Schreeder MT, Steis RG, Guidice RA, et al. Cetuximab in combination with carboplatin and docetaxel for patients with metastatic or advanced-stage nonsmall cell lung cancer: a multicenter phase 2 study. Cancer. 2008 Nov 1;113(9):2512-7
• Borghaei H, Langer CJ, Millenson M, Ruth KJ, et al. Phase II study of paclitaxel, carboplatin, and cetuximab as first line treatment, for patients with advanced non-small cell lung cancer (NSCLC): results of OPN-017. J Thorac Oncol. 2008 Nov;3(11):1286-92

Images courtesy American Society of Clinical oncology (ASCO)