Novel Cancer Drug Test May Results in Safer and More Effective Clinical Trials

A group of scientists from Hamburg may have taken a big step towards more effective cancer drug development. Dr Ilona Schonn, Director of Cell Culture Research at Indivumed GmbH, a company specialized in the analysis and procurement of highly standardized tissue samples and data of tumor patients, told the audience at Europe’s largest cancer congress, the joint 15th European CanCer Organisation (ECCO) and 34th European Society for Medical Oncology (ESMO) Multidisciplinary Congress, September 20 – 24 in Berlin, Germany, that they had developed a preclinical drug test platform that would enable researchers to analyze tumor tissue for individual patient drug responses on the molecular level.

To date most tests for drug metabolism and toxicity testing have used tissue slices of normal organs like liver, kidney and lung. The new test was created specifically for oncology drug testing and uses tumor tissues from colorectal and lung cancer patients.

A major problem of drug development at present is the inability to extrapolate response in preclinical cell models to patients. “Approximately 90% of clinical trials fail because the drugs used are too ineffective or too toxic,” explained Dr Schonn. “Not only does this result in unacceptably high costs for drug development, but it also exposes patients to risks from toxicity or simply wastes their time in testing a substance which proves to be ineffective.”

The problem arises from the fact that patients respond individually to drugs. In addition, each tumor consists of a variety of different cancer cells that interact in different ways with the framework of individual non-tumor cells, resulting in highly variable growth behavior and response to drugs. Dr Schonn and her team set out to try to develop a drug test that would eliminate these problems and provide an accurate model of individual patient response.

“Based on freshly cultivated intact tissue from surgically treated cancer patients we are now able to analyze numerous tumors from different patients, to identify differences in drug response between those patients, and to understand variations of response in cell subtypes within one tumor,” said Dr Schonn.

The new test allows scientists to translate findings from commonly used cell lines to a preclinical model which is as close as possible to using the same drug in the clinical setting, thus enabling a better estimate of the number of patients who are likely to respond to the treatment. It also helps to identify biomarkers that can predict drug response for patients entering a clinical trial, allowing researchers to include only those patients whose participation will provide a significant answer to the question being asked.

“Together with all the clinical patient data and several analytical test systems such as signaling pathway analysis, we have been able to characterize individual tumors in more detail. This will improve the understanding of drug effects and treatments, a step forward towards the goal of individualized cancer therapy,” she said. “The test is of particular interest to pharmaceutical companies because it allows the analysis of samples from meaningful number of patients with different tumors in a short period of time, and can, therefore, accelerate progression of a potential new treatment to clinical trials.”

In addition, it can help gain more knowledge about the mode of action of a new compound in patients, and identify optimal disease areas, for example tumors with particular mutations or over-expression of target receptors, and dosage.

To date the test has only been validated in colon, non-small cell lung (NSCLC), and breast cancer tumors but there is no reason to think that it would not be equally accurate in other solid tumor types, the scientists say.

“Because the test allows us to maintain the complex environment of the primary cancer tumor, we believe that it holds out great promise for the quick and effective elucidation of response to anticancer drugs,” said Dr Schonn. “We hope to be able to apply it to a growing number of drugs emerging from the labs of pharmaceutical companies to help to shorten development time and to make clinical trials both more efficient and safer for patients.”

The test can analyze numerous tumors from different patients, identify the patients’ diverse reactions to the test compounds and elucidate their varying effects on cell subtypes within the same tumor. Says Prof Dr Hartmut Juhl, CEO and founder of Indivumed. “In the long run, our test paves the way to personalized medicine, because it helps to understand and to embrace the individual reactions of the patients to a certain therapy.”

For more information:

• Abstract no: 1013, Basic Science/Translational Research poster discussion, Wednesday 17.00 – 18.00 hrs CEST (Hall 14.2)

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)

Diagnostic Test to Select Patient Candidates for Novel Investigational Non-Small Cell Lung Cancer Therapy

Abbott's molecular diagnostics business, headquartered in Des Plaines, Ill.,has entered into an agreement with Pfizer Oncoloy, a business unit of Pfizer Inc, committed to the discovery, investigation and development of innovative treatment options for cancer patients worldwide, to develop a molecular diagnostic test intended to screen non-small cell lung cancer (NSCLC) tumors for the presence of gene rearrangements.

Pfizer has developed a novel investigational agent that selectively targets cancer-causing genes implicated in the progress of many cancers. To be eligible to receive Pfizer's oral therapy, a particular genetic translocation (rearrangement) known to be found in NSCLC tumors and a wide variety of other cancers, but not in normal cells, must be present.

Under terms of the agreement, Abbott will develop a companion diagnostic test that will determine a patient's genetic status and will be used in patient selection for future clinical trials of PF-02341066.

"We are very pleased to partner with Abbott to develop a companion diagnostic test for non-small cell lung cancer and ensure its global availability for patients and physicians who need this information to make the best treatment decisions," said Garry Nicholson, General Manager, Pfizer Oncology Business Unit.

"This test will allow us to focus on the patient population most likely to benefit from our NSCLC candidate. Working in close partnership with the experienced Abbott team, we are confident that we will deliver yet another application of personalized medicine to address a currently unmet medical need in NSCLC."

"Pfizer's novel compound for treating non-small cell lung cancer appears to be ideally suited to individualized therapy," said Stafford O'Kelly, head of Abbott's molecular diagnostics business. "Abbott is a leader in the development and commercialization of companion diagnostics and we're delighted to collaborate with Pfizer, a leader in cancer therapeutics, on the development of a test to identify patients who might benefit from this important compound."

Erlotinib Improves Overall Survival After Initial Chemotherapy in Patients with Advanced Lung Cancer

Results from SATURN, a pivotal Phase III study, met a key secondary endpoint of extending overall survival in patients with advanced non-small cell lung cancer (NSCLC) who received erlotinib (Tarceva®, Genentech/Roche; OSI) immediately after their initial chemotherapy. A statistically significant improvement in overall survival was seen in the pre-planned final analysis of the total patient population in the study. The new data will be presented during the 13th World Conference on Lung Cancer to be held July 31 – August 4, 2009 in San Francisco.

Lung cancer is the most common cancer worldwide with 1.5 million new cases annually and NSCLC accounts for 85 – 90% of all lung cancers. Non-small cell lung cancer (NSCLC) progresses rapidly and survival rates are generally very poor. Most people are diagnosed with advanced stage disease and less than 5% of these advanced NSCLC patients survive for five years. Extending the time patients live and managing side effects are key treatment goals.

According to the American Cancer Society, lung cancer is the leading cause of cancer death in the United States. In 2009, approximately 159,000 Americans will die from the disease.
Treating patients immediately following first-line chemotherapy versus waiting for the cancer to grow or spread before giving additional treatment represents a new approach in advanced NSCLC.

A new approach
Erlotinib is, as a Human Epidermal Growth Factor Receptor Type 1/Epidermal Growth Factor Receptor (HER1/EGFR) tyrosine kinase inhibitor, different from conventional chemotherapies.
Over-expression of EGFR is common in several solid tumors, such as colorectal cancer, lung carcinomas, and cancers of the head and neck. It correlates with increased metastasis, decreased survival and a poor prognosis. EGFR protects malignant tumors cells from the cytotoxic effects of chemotherapy and radiotherapy, making these treatments less effective.

HER1 and EGFR receptors are directly involved in inter-cellular signaling in systems governing cell division and proliferation. By interfering with the function of these receptors, which are highly active and often over-expressed in rapidly dividing tumor cells, erlotinib inhibits EGFR-receptor tyrosine kinase activity, and may help to initiate pathways of apoptotic cell death. The interference with the cell signaling pathways involved in cell proliferation represents a novel approach to the treatment of solid tumors.

Today, erlotinib is the first and only EGFR oral targeted agent in second line with a proven and significant survival and symptom benefit in a broad range of patients with advanced lung cancer without the side effects associated with chemotherapy. The drug has been approved in the EU since September 2005 and in the US since November 2004 for the treatment of patients with locally advanced or metastatic NSCLC after failure of at least one prior chemotherapy regimen.

Patient benefit
In the landmark registration study BR.21, a randomised controlled phase III clinical trial comparing erlotinib with placebo/best supportive care in patients with locally advanced or metastatic non-small lung cancer which took place in 17 countries around the world, erlotinib delivered effectiveness comparable to chemotherapy and significantly improves overall quality of life.

The registration study underlined that more patients on erlotinib had improvement in cough, pain, shortness of breath and overall physical function versus patients on placebo. In addition erlotinib did not induce the distressing side-effects associated with chemotherapy, such as nausea and vomiting. An added benefit, improving adherence, is that erlotinib is convenient as patients can take a tablet once a day at home rather than receive intravenous treatments in a hospital.

Global trial
SATURN, a global multicentre, double blind, randomized, prospective phase III study was designed to evaluate the efficacy of erlotinib vs. placebo in patients with advanced, recurrent or metastatic NSCLC who had not progressed following first line platinum-based chemotherapy. The study involved more than 880 patients from approximately 160 centers; 438 received erlotinib and 451 placebo.

The study met its primary endpoint demonstrating a statistically significant extension of the time patients live without their disease worsening; there was a 41% increase compared with placebo (hazard ratio= 0.71, p-value <0.0001).>

“This study has now not only confirmed that immediate treatment with Tarceva after initial chemotherapy delayed the progression of disease, but also importantly helped patients in the study live longer,” said Professor Federico Cappuzzo, M.D., Istituto Clinico Humanitas IRCCS, Milan and principal investigator of the SATURN study. “This is good news for doctors and their patients since advanced lung cancer is one of the most challenging cancers to treat and is often associated with a very short life-expectancy.”

Commenting on the study, William M. Burns, CEO Division Roche Pharmaceuticals said, “This is the second set of data from large studies that has shown Tarceva helps patients with advanced lung cancer to live longer. These results confirm that Tarceva has an important role to play in improving the lives of patients earlier in the management of this devastating disease.”

Erlotinib is already a well established treatment in second-line management of advanced NSCLC after the failure of chemotherapy and is proven to extend survival for a broad range of patients in this setting. Most recently, presentation of the SATURN primary endpoint data analysis at ASCO 2009 showed that patients who received treatment with erlotinib immediately after initial chemotherapy if their cancer had not progressed had a 41% improvement in the length of time they lived without their disease getting worse compared to placebo.

Outcome confirmed
During the Annual Society of Clinical Oncology (ASCO) Vincent A. Miller, MD., a medical oncologist from the Memorial Sloan-Kettering Cancer Center, presented results from the phase III ATLAS study supported findings in the SATURN study.

The ATLAS study, a global multicentre, randomised, double blind, placebo controlled study that enrolled 1,160 patients with locally advanced, recurrent or metastatic NSCLC, was designed to evaluate bevacizumab (Avastin®, Genentech/Roche) in combination with erlotinib (150 mg daily) versus bevacizumab alone, following bevacizumab in combination with a platin-containing doublet chemotherapy, in patients with stage IIIb/IV NSCLC.

The study showed that combined treatment with bevacizumab and erlotinib, immediately following initial therapy with bevacizumab plus chemotherapy was highly effective and significantly delayed disease progression for patients with advanced NSCLC, without the need for chemotherapy.

The positive results from these trials were encouraging because previous Phase III studies in which erlotinib was used as first-line therapy in combination with cytotoxic drugs (the TRIBUTE and TALENT studies) failed to demonstrate a survival advantage when erlotinib was added to conventional treatment regimens.

The overall survival data fron SATURN will be used to support the European and US applications for use of erlotinib as a first-line maintenance treatment for patients with advanced NSCLC. These applications were made to the European Medicines Agency (EMEA) and US Food and Drug Administration (FDA) in March 2009 and are based on the pivotal Phase III SATURN trial. The FDA Prescription Drug User Fee Act (PDUFA) review date will be on or about January 18, 2010.

Commenting on the overal product development, Colin Goddard, Ph.D., Chief Executive Officer of OSI Pharmaceuticals, Roche's US partner, said:"We are pleased with the launch of Tarceva in the U.S. to date and we continue to believe that Tarceva will emerge as a fundamentally important new agent in changing the paradigm for the treatment of cancer patients around the world. With our partners, Genentech and Roche, we are committed to executing a post-approval development plan, studying Tarceva in earlier stage lung cancer patients, in patients with other tumor types and combinations with other targeted therapies."

For more information:

• Gatzemeier U, Pluzanska A, Szczesna A, Kaukel E, Roubec J, et al. Phase III Study of Erlotinib in Combination With Cisplatin and Gemcitabine in Advanced Non–Small-Cell Lung Cancer: The Tarceva Lung Cancer Investigation Trial. Journal of Clinical Oncology, Vol 25, No 12 (April 20), 2007: pp. 1545-1552.
• Herbst RS, Prager D, Hermann R, Fehrenbacher L, Johnson BE, et al. TRIBUTE: A Phase III Trial of Erlotinib Hydrochloride (OSI-774) Combined With Carboplatin and Paclitaxel Chemotherapy in Advanced Non–Small-Cell Lung Cancer. Journal of Clinical Oncology, Vol 23, No 25 (September 1), 2005: pp. 5892-5899.
• National Cancer Institute: Erlotinib (Tarceva®) Extends Survival in Advanced Lung Cancer
• Tarceva (erlotinib) USA website for healthcare professionals
• Tarceva (erlotinib) Global website for healthcare professionals
• Garcia M et al. Global Cancer Facts & Figures. Atlanta, GA: American Cancer Society, 2007.
• Highlights of Prescribing Information (USA)

ASCO 2009 Annual meeting:

• Cappuzzo F, Ciuleanu T, Stelmakh L, Cicenas S, Szczesna A, et al. SATURN: A double-blind, randomized, phase III study of maintenance erlotinib versus placebo following nonprogression with first-line platinum-based chemotherapy in patients with advanced NSCLC. J Clin Oncol 27:15s, 2009 (suppl; abstr 8001). Abstract presented at ASCO 2009 Annual Meeting, Orlando.
• Miller VA, O'Connor P, Soh C, Kabbinavar F. A randomized, double-blind, placebo-controlled, phase IIIb trial (ATLAS) comparing bevacizumab (B) therapy with or without erlotinib (E) after completion of chemotherapy with B for first-line treatment of locally advanced, recurrent, or metastatic non-small cell lung cancer (NSCLC). J Clin Oncol 27:18s, 2009 (suppl; abstr LBA8002). Abstract presented at ASCO 2009 Annual Meeting, Orlando.

Also read these PubMed abstracts:

• Allen J, Jahanzeb M. Neoadjuvant chemotherapy in stage III NSCLC. J Natl Compr Canc Netw. 2008 Mar;6(3):285-93.
• Brown ER, Shepherd FA. Erlotinib in the treatment of non-small cell lung cancer. Expert Rev Anticancer Ther. 2005 Oct;5(5):767-75. Review.
• Shepherd FA, Rodrigues Pereira J, Ciuleanu T, Tan EH, Hirsh V, et al. Erlotinib in Previously Treated Non–Small-Cell Lung Cancer. N Engl J Med 2005; 353:123-132. (See also Full Text Article)
• Tsao MS, Sakurada A, Cutz JC, Zhu CQ, Kamel-Reid S, et al. Erlotinib in Lung Cancer — Molecular and Clinical Predictors of Outcome. N Engl J Med. 2005 Jul 14;353(2):133-44 (See also Full Text Article).
• Sandler A. Clinical experience with the HER1/EGFR tyrosine kinase inhibitor erlotinib. Oncology (Williston Park). 2003 Nov;17(11 Suppl 12):17-22

Information for your patient:

• Tarceva (erlotinib) USA patient website.
• Tarceva (erlotinib) Global patient website.

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)

Lipocalin 2 promotes breast cancer progression: Breast Cancer Biomarker Highlighted as useful in Non-Invasive Diagnostic Assays

Lipocalin-2 (lcn2) a 25 kDa secretory glycoprotein, also called NGAL (neutrophil gelatinase-associated lipocalin) is predominantly expressed in adipose tissue and liver and belongs to the lipocalin superfamily that consists of over 20 small secretory proteins. Lipocalin folds consist of 8 antiparallel ß-sheets that surround a hydrophobic pocket. A common feature of this protein family, following from its structure, is its capacity to bind and transport small lipophilic substancies such as free fatty acids, retinoids, arachidonic acid and various steroids.

Although Lipocalin-2 was identified more than a decade ago, the physiologic function of this protein remained poorly understood. Research now showd that lipocalin-2 appears to be upregulated in cells under the “stress” (e.g. from infection, inflammation, in tissues undergoing involution to ischemia or neoplastic transformation).

Therapeutic importance
Plasma levels of lipocalin-2 rise in inflammatory or infective condition. The protein mediates an immune response to bacterial infection by sequestering iron. Therfore, Lipocalin-2 may represent a promising candidate as a therapeutic agent against bacterial infection.
Several recent reports suggest that lipocalin-2 may also represent a sensitive biomarker for early renal injury. In cardiopulmonary bypass-induced acute renal injury and cisplatin-induced nephrotoxic injury, increased de novo synthesis of lipocalin-2 in proximal tubule cells leads to sharply increased concentration of this protein in both urine and serum.

Lipocalin-2 is also highly expressed after malignant transformation of the lung, colon and pancreatic epithelia. Circulating levels of lipocalin-2 play a causative role in pathogenesis of obesity-induced metabolic disorders such as insulin resistance, Type 2 Diabetes Mellitus and cardiovascular disorders. In addition, serum lipocalin-2 concentrations were positively associated with adipocyte-fatty acid binding protein (A-FABP), a novel serum marker for adiposity and metabolic syndrome.

Role in Breast Cancer
Reserach show that lipocalin-2 plays an important role in breast cancer, in complex with matrix metalloproteinase-9 or MMP-9, by protecting MMP-9 from degradation thereby enhancing its enzymatic activity and facilitating angiogenesis and tumor growth.

Researchers demonstrated that the binding of neutrophil gelatinase-associated lipocalin (NGAL) to matrix metalloproteinase-9 (MMP-9) protects the extracellular matrix remodeling enzyme from autodegradation. Although breast cancer cells express MMP-9 and not the NGAL protein, clinical researchers hypothesized that the addition of NGAL to breast cancer cells, result in a more aggressive phenotype in vivo. Based on previous reports that MMPs can be detected in the urine of cancer patients, researchers wondered whether MMP-9/NGAL could be detected in the urine of breast cancer patients and whether it might be predictive of disease status.

In an article by Yang, Bielenberg, Rodig and colleagues published in the Proceedings of the National Academy of Sciences (PNAS) investigating the function of lipocalin 2 in breast cancer progression, the research team identified the mechanisms in which lipocalin 2 promotes breast cancer progression.

Yang and colleagues noted that lipocalin-2 levels were consistently associated with invasive breast cancer in human tissue and urine samples. In research designed to unravel the role of Lipocalin 2 was overexpressed in human breast cancer cells and was found to up-regulate mesenchymal markers, including vimentin and fibronectin, down-regulate the epithelial marker E-cadherin, and significantly increase cell motility and invasiveness.

These changes in marker expression and cell motility are hallmarks of an epithelial to mesenchymal transition (EMT). Reserachers also noted that Lcn2 silencing in aggressive breast cancer cells inhibited cell migration and the mesenchymal phenotype. Furthermore, reduced expression of estrogen receptor (ER) α and increased expression of the key EMT transcription factor Slug were observed with lipocalin-2 expression.

Overexpression of ERα in Lcn2-expressing cells reversed the EMT and reduced Slug expression, suggesting that ERα negatively regulates Lcn2-induced EMT. Finally, orthotopic studies demonstrated that Lcn2-expressing breast tumors displayed a poorly differentiated phenotype and showed increased local tumor invasion and lymph node metastasis.

A non-invasive biomarker for advanced breast cancer
In this research, Yang demonstrated that lipocalin 2 promotes breast cancer progression by inducing the epithelial to mesenchymal transition (EMT), one of the key processes involved in tumor progression and metastasis. The team further showed that lipocalin-2 levels can be measured in urine samples, and high levels are correlated with cancer cell migration and invasiveness in women with advanced or metastatic estrogen-receptor (ER)-negative breast cancer.

These findings suggest the potential for lipocalin 2 as a non-invasive biomarker for advanced breast cancer. lipocalin-2, along with other urine biomarkers for various cancers discovered at Children’s Hospital Boston, is exclusively licensed to Predictive Biosciences for diagnostic assay development. Predictive Biosciences is an emerging molecular diagnostics company developing non-invasive diagnostic products for informed cancer management™.

"Estrogen-receptor negative breast tumors are among the most difficult to treat," said Marsha A. Moses, Ph.D., Professor of Surgery at Harvard Medical School and interim Director of the Vascular Biology Program at Children’s Hospital Boston, and co-author of the PNAS publication. Dr. Moses, a co-founder of Predictive Biosciences / , added, "We are excited by this research showing a strong correlation between high levels of Lcn2 and the aggressiveness of breast cancer. These studies suggest the potential for a simple, urine-based assay to measure Lcn2 as a way of monitoring cancer development and progression on an individual basis, and to determine if more aggressive treatment is needed. This would be an important step towards more accurate and personal cancer management for these patients."

Utilizing its portfolio of patented biomarkers and proprietary clinical approaches (such as Clinical Intervention Determining Diagnostic™ or CIDD); Predictive Biosciences is developing novel diagnostic assays that have exceptionally high negative predictive value (NPV) and positive predictive value (PPV) for cancer development and progression. This information, incorporated into current standard clinical practice, should lead to more effective utilization of existing tools and ultimately better outcomes for patients. Predictive aims to deliver highly accurate, convenient diagnostics to provide physicians with actionable information for personalized diagnostic follow-up and treatment plans – avoiding expensive, invasive procedures and increasing patient compliance and comfort.

"We are very pleased to be collaborating with Professor Marsha Moses and Children’s Hospital Boston on developing a number of urine-based cancer diagnostic assays," said Peter Klemm, Ph.D., President and Chief Executive Officer of Predictive.

"Already, Predictive is advancing novel bladder cancer assays, with plans to commercialize these tests via our CLIA lab. In addition, we have a rich pipeline of biomarkers poised for diagnostic assay development, including this very compelling breast cancer biomarker, Lcn2. Leveraging our deep clinical development and scientific capabilities, we are building a robust portfolio of innovative cancer assays, in collaboration with others who share our interest in delivering highly accurate and convenient cancer diagnostics for informed cancer management™."

For more information also read these PubMed abstracts:

• Yang J, Bielenberg DR, Rodig SJ, Doiron R, et al. Lipocalin 2 promotes breast cancer progression. Proc Natl Acad Sci U S A. 2009 Mar 10;106(10):3913-8. Epub 2009 Feb 23.
• Fernández CA, Yan L, Louis G, Yang J et al. The matrix metalloproteinase-9/neutrophil gelatinase-associated lipocalin complex plays a role in breast tumor growth and is present in the urine of breast cancer patients. Clin Cancer Res.2005 Aug 1;11(15):5390-5 (Full article)
• Søiland H, Skaland I, Varhaug JE, Kørner H, et al. Co-expression of estrogen receptor alpha and Apolipoprotein D in node positive operable breast cancer--possible relevance for survival and effects of adjuvant tamoxifen in postmenopausal patients. Acta Oncol. 2009;48(4):514-21.
• Shi H, Gu Y, Yang J, Xu L, Mi W, Yu W. Lipocalin 2 promotes lung metastasis of murine breast cancer cells. J Exp Clin Cancer Res. 2008 Dec 12;27:83.
  

New Studies Help Advance Understanding and Treatment of Lung Cancer

Findings from several large studies on lung cancer were released at the 45th Annual Meeting of the American Society of Clinical Oncology (ASCO), being held in Orlando, Florida, from May 27 – June 2, 2009.

Today, 1.3 million new cases of lung cancer are diagnosed every year around the worls. The vast majority of lung cancers are caused by cigarette smoking. In the United States 350,000 people are living with lung cancer at any given time. Until the late 1990s, lung cancer was the most frequently occurring cancer in the UK. It has now been overtaken by breast cancer, but still accounts for around 1 in 7 new cancer cases.

In recent years, better diagnostics, reduction in smoking and better treatment options have resulted in a lower number of new cases and reported deaths. But regardless these improvements, lung cancer remains the second most common of diagnosed cancers and the number one of cancer-related deaths in the U.S.

“Lung cancer is one of the most challenging cancers to treat, but the studies presented during the annual ASCO-meeting highlight promising new targeted therapies and milder treatment regimens that improve survival,” said Bruce E. Johnson, MD, Director of the Dana-Farber Harvard Medical Center Lung Cancer Program.

Researchers also report that hormone therapy among menopausal women with lung cancer is associated with a higher risk of death. These findings add to growing concerns about the safety of hormone therapy. The studies being highlighted in OncoZine – The International Cancer Blog include:

• Pemetrexed extends survival as maintenance therapy: A phase III study reports that maintenance therapy with pemetrexed (Alimta, Eli Lilly and Company) improves overall survival in nonsquamous forms of advanced non-small cell lung cancer (NSCLC).
• Maintenance therapy with two targeted therapies is superior to one alone: A phase III trial finds that adding erlotinib (Tarceva, Genentech/Roche) to bevacizumab-based (Avastin, Genentech/Roche) maintenance therapy in patients with advanced NSCLC delays cancer progression more than maintenance treatment with bevacizumab alone.
• Menopausal hormone therapy with estrogen and progestin linked to increased risk of death in women with lung cancer: A secondary analysis from the Women’s Health Initiative reports that use of hormone therapy with estrogen plus progestin increases the risk of dying from NSCLC for women with the disease.
• Novel therapy that targets two receptors benefits patients with advanced lung cancer: A phase III trial demonstrates that vandetanib (Zactima, AstraZeneca), a novel drug that targets two key receptors associated with lung cancer growth, improves progression-free survival in patients with advanced NSCLC.

For more information:

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

Reference:

• The International Medical-Oncology Library (at Boomja.com)

Drug information:

• Pemetrexed (Alimta, Eli Lilly and Company)
• Erlotinib (Tarceva, Genentech/Roche)
• Bevacizumab (Avastin, Genentech/Roche)
• Vandetanib (Zactima, AstraZeneca)

General information:

• Lung Cancer Alliance.
• The Wellness Community.
• American Cancer Society. How Is Non-Small Cell Lung Cancer Diagnosed? Common Signs and Symptoms of Lung Cancer.
• Cancer Research UK – Lung Cancer at a Glance

Illustration courtesy of the American Society of Clinical Oncology.

European specialists are joining forces to improve lung cancer treatment

Prevention, personalized therapies and closer collaborations between surgeons, medical oncologists and radiation oncologists will result in better outcomes for lung cancer patients and those at risk, a leading European expert says.

“Lung cancer is a complex disease. It is one of the most complex cancers, and the more we learn about the biology of the disease, the more we realize that improved cancer care will result from multidisciplinary treatment,” said Prof Robert Pirker, from the Medical University of Vienna, Austria (Spitalgasse 231090 Wien 9., Alsergrund, Wien, Austria). Prof Pirker is co-chair of the scientific committee of a new medical conference, the European Multidisciplinary Conference in Thoracic Oncology (EMCTO), being held for the first time this year, 1-3 May, at the Palazzo dei Congressi in Lugano, Switzerland.

The conference aims to further clinical and scientific cooperation between disciplines to help in the fight against lung cancer. Designed as a regular multidisciplinary, educational meeting, the organizers feel that the meeting may help strengthening general knowledge and providing an updated overview of prevention, screening, diagnosis, treatment modalities and results of translational research. One of the goals of the organizers is to facilitate interaction between the specialties in order to promote an integrated approach to diagnosis and treatment of chest tumors and to strengthen European cooperation and scientific exchange in multidisciplinary management of lung cancer.

A common cancer
Lung cancer is the most common cancer in the world. In men, the highest incidence rates are seen in Europe (especially eastern Europe) and North America. In women, high incidence rates are found in North America and in Europe, particularly in northern and western Europe.

Role of tobacco and smoking
Tobacco smoking is well established as the main cause of lung cancer and about 90% of cases are thought to be tobacco related. There is a clear dose-response relation between lung-cancer risk and the number of cigarettes smoked per day, degree of inhalation, and age at initiation of smoking. Researchers have noted that someone who has smoked all his life has a 20 -30 times greater risk of getting lung-cancer than a non-smoker. The link between tobacco-use and smoking is further emphasized by the fact that the risk of lung cancer decreases with time since smoking cessation.

Research has also shown that while the incidence of lung cancer among men in many Western European countries has been decreasing since the 1980s, the age-adjusted rate for men in other European countries increased at least until the 1990s. Among women this peak in incidence had not been reached in the 1990s. At the same time, the proportion of adenocarcinoma in both men and women has been increasing over time. The most likely explanation for this trend is the shift to low-tar filter cigarettes.

Screening Emphasized
Since the early 2000’s there has been renewed interest in screening because spiral computerized tomography (CT) can detect small asymptomatic lesions more effectively than conventional radiography. Although cure rates for such lesions are very good, there is to date no evidence for effectiveness of mass-screening strategies.

Targeted therapies
Over the past 5 years, researchers have established that for patients with operable cancer, surgery followed by chemotherapy can result in good outcomes. Now, large clinical trials are beginning to evaluate that adding molecular targeted therapies can further improve the chance of a successful outcome for some patients. In addition, doctors are now attempting to refine their treatments based on the clinical characteristics of individual patients, and based on the molecular profile of their tumor.

“More sophisticated and complex treatments require more cooperation,” Prof Pirker says. “That is one of the reasons why we have organized this conference. We believe the result will be better outcomes for lung cancer patients.”

For patients with metastatic disease, targeted therapies have already entered clinical practice or have shown survival benefit in clinical trials. Combinations of chemotherapy and radiotherapy are also improving outcomes of loco-regional non-small-cell lung cancer. “Cure is now possible in about 15% to 20% of patients whose disease can be treated in this way,” adds Prof Jean-Paul Sculier, from Institut Jules Bordet in Brussels, Belgium. (121 Boulevard de Waterloolaan, Bruxelles 1000 Brussel 121 Boulevard de Waterloolaan, Bruxelles 1000 Brussel, telephone +32 254 1311). Prof Sculier will chair a session on treating advanced disease at the conference.

During the European Multidisciplinary Conference in Thoracic Oncology Research groups will present new data that reflect these developments, including:

• A study comparing radiotherapy alone to sequential chemotherapy and radiation in locally advanced non-small-cell lung cancer, plus a correlation of gene expression level with survival (UK).
• Promising results from a study of accelerated hypofractionated three-dimensional conformal radiotherapy (3D-CRT) with dose-per-fraction escalation for treatment of stage III non-small-cell lung cancer (Poland).
• Confirmation that EGFR mutations (deletion in exon 19, missense L858R) are the most important predictors of sensitivity to tyrosine-kinase inhibitor targeted therapies (Italy)
  

Barbara Zolty from the World Health Organization (Avenue Appia 20 1211 Geneva 27 Switzerland telephone +4122791211) will also highlight the importance of preventing lung cancer as the first and foremost weapon against lung cancer. Ms Zolty will speak about the WHO Tobacco-Free Initiative with an enlightening keynote lecture entitled “A thousand seconds, a thousand lives.”

The EMCTO Conference is co-organized by the European Society for Medical Oncology (ESMO), the European Society for Therapeutic Radiology and Oncology (ESTRO), the European Society of Thoracic Surgeons (ESTS) and the European Respiratory Society (ERS)

For more information also read:

• Janssen-Heijnen ML and Coebergh JW, The changing epidemiology of lung cancer in Europe, Lung Cancer. 2003 Sep;41(3):245-58 )
  

Combining targeted therapy drugs may treat previously resistant tumors

Blocking two cell signaling pathways leads to dramatic shrinkage of K-Ras-mutated tumors in animal model. This is the conclusion of a team of cancer researchers from several Boston academic medical centers. The team believes that their findings offer a potential treatment for a group of tumors that have resisted previous approaches of treatment with selected targeted therapies.

In their report published in the december issue of Nature Medicine, investigators from Dana-Farber Cancer Institute, a principal teaching affiliate of the Harvard Medical School, Massachusetts General Hospital (MGH) Cancer Center, the original and largest teaching hospital of Harvard Medical School and Beth Israel Deaconess Medical Center (BIDMC) Cancer Center, a patient care, teaching and research affiliate of Harvard Medical School, report that combining two different kinase inhibitors, drugs that interfere with specific cell-growth pathways, led to significant tumor shrinkage in mice with lung cancer driven by mutations in the K-Ras gene.

K-ras, which is part of the ras family of oncogenes which also includes H-ras and N-ras, is involved in the development of a variety of human malignancies. The K-ras oncogene resides on chromosome 12p12, and encodes a 21-kD protein (p21ras) involved in the G-protein signal transduction pathway, modulating cellular proliferation and differentiation. The ras pathway is important in the transmission of growth-promoting signals from the cell surface receptors and affect the production and regulation of key proteins. Mutations of the K-Ras gene occur long before the formation of the actual cancer.

Controversial
So far, researchers believe that the clinical significance of K-ras mutations is somewhat controversial. But a number of studies have shown lower median survival times in patients with mutation-positive tumors in gastrointestinal malignancies. As it turns out, K-ras mutations are one of the most common genetic abnormalities in colon, pancreatic cancers and bile duct carcinomas, detectable in greater than 75% of tumors. These cancers are extremely resistant to treatment.

In gynecological malignancies and endometrial carcinomas, K-ras mutations are noted in up to a third of cases. Studies have shown that in postmenopausal women with endometrial carcinomas, K-ras mutations appear to be an independent risk factor for adverse prognosis. Researchers believe that that the presence of K-ras mutations in endometrial hyperplasia specimens may identify a group of patients with a high probability for progression.

K-ras mutations are also associated with nearly 30% of non-small-cell lung cancer, the leading cause of cancer deaths in the United Sates. In limited stage adenocarcinomas, usually is seen peripherally in the lungs, the presence of K-ras mutation is independently associated with more aggressive disease and decreased patient survival.

"Finding a way to effectively treat K-Ras-mutated cancers would be a huge advance in solid tumor oncology, since these mutations are common in several incurable cancers," explained Jeffrey Engelman, MD, PhD, of the MGH Cancer Center, one of the report's co-lead authors. "Cancers with K-Ras mutations have been resistant to all targeted therapies to date, and it is exciting to learn that a combination of PI3K and MEK inhibitors, two families of drugs currently in clinical development, may be highly effective in these cancers."

The current study began with a focus on the PI3K signaling pathway, which is key to cell survival and known to control cellular motility and adhesion. PI3K mutations have caused tumor development in laboratory studies, but their role had not yet been studied in an animal model. The research team developed a transgenic mouse in which administration of the drug doxycycline induces the expression of cancer-associated PI3K mutations, leading to development of lung tumors.

Treatment of those animals with an investigational PI3K inhibitor did lead to rapid tumor regression. Since previous studies suggested that PI3K inhibition might also block K-Ras-induced tumor development, the investigators also tested the PI3K inhibitor in mice with K-Ras-stimulated tumors.

That treatment was ineffective, but since K-Ras also activates the MEK/ERK signaling pathway, the researchers treated the animals with an investigational MEK inhibitor and with a combination of both drugs. Treatment with the MEK inhibitor alone caused only a modest reduction in tumor size, but combined treatment with both agents caused the K-Ras-stimulated lung tumors to virtually disappear.

"For several years we have known that K-Ras activates two major pathways — the PI3K pathway and the MEK/MAPK pathway — and that these pathways have many redundant functions in tumor growth and survival," notes Lewis Cantley, PhD, of the BIDMC Cancer Center, one of the study's co-corresponding authors. Contley continues: "Inhibitors of both of these pathways are now in clinical trials, and in this paper we show that, while either agent alone has a minor effect on K-Ras-driven tumors in mice, combining inhibitors of both pathways eradicates these tumors with minimal toxicity."

Kwok-Kin Wong, MD, PhD, of Dana-Farber, also a co-corresponding author, adds, "The results of our study are truly remarkable and provide a strong and compelling scientific rationale to test this combination therapy in human phase 1 and 2 trials. This work would not have been possible without the highly productive collaboration between our laboratories at Mass. General, Beth Israel Deaconess and Dana-Farber."

Wong is an assistant professor of medicine at Harvard Medical School, where Engelman is also an assistant professor in medicine and Cantley is the Castle Professor of Medicine.

The researchers are hoping to advance towards clinical trials by testing combination therapy against other models of K-Ras-mutated cancer, including those that involve additional mutations in other tumor-associated genes, and to investigate whether K-Ras-associated tumors will become resistant to combination therapy, a problem that has plagued other targeted cancer therapies.

Also read PubMed abstracts:

• Engelman JA, Chen L , Tan X, Crosby K et al. Effective use of PI3K and MEK inhibitors to treat mutant Kras G12D and PIK3CA H1047R murine lung cancers. Na. Med 2008 Dec;14(12):1351-1356. Epub 2008 Nov 30.
• Zhao L, Vogt PK. Class I PI3K in oncogenic cellular transformation. Oncogene 2008 Sep 18;27(41):5486-96.
• Yuan TL, Cantley LC . PI3K pathway alterations in cancer: variations on a theme. Oncogene 2008 Sep 18;27(41):5497-510.