A 44-year old patient with inflammatory myofibroblastic tumor (IMT), a sarcoma that predominantly develops in the abdomen or chest of young adults and children, was found to respond surprisingly well to a new oral medication with “dramatic shrinkage” of tumors, researchers from the Dana-Farber Cancer Institute wrote in the NEJM (New England Journal of Medicine). This rare cancer thrives on a mutant protein. The researchers reveal that another patient with a similar tumor that did not need the mutant protein to survive and progress did not respond to the medication, confirming the medication’s specific targeting of that protein – inhibiting it.
The authors write that this study shows how personalized medicine gene-testing is the way to go in order to find the best tailored treatment for each patient’s genetically defined cancer.
The mutant protein is called ALK (anaplastic lymphoma kinase, the first disease where it was found).
In about half of all patients with inflammatory myofibroblastic tumor (IMT), ALK binds to another protein in the cancer cells, encouraging the development of cancer. After standard chemotherapy medications followed by Gleevec, the patient had subsequently experienced cancer recurrence with multiple tumors.
James Butrynski, MD and Geoffrey Shapiro, MD, PhD told the patient he could take part in a Phase 1 trial of crizonib, an experimental medication that blocks ALK activity. Crizonib also inhibits MET, an oncogene that is abnormally activated in some cancers.
After taking the experimental drug, the patient’s tumor shrank by over 50%, what doctors call a “partial response”. By December 2008, several months into crizotinib treatment, a number of tumors started growing – they had developed resistant to the drug’s effects. The doctors surgically removed the tumors, including those that continued to be responsive to crizotinib. After surgery the patient resumed crizotinib treatment. The researchers report that in September 2010 the patient continued without any evidence of the cancer.
In another study, scientists from Massachusetts General Hospital, Dana-Farber/Brigham and Women’s Cancer Center, and some other hospitals reported in the NEJM how crizotinib shrank tumors in patients with NSCLC (non-small cell lung cancers) – their tumors also contained the mutant ALK protein.
82 patients with NSCLC who had not responded adequately to standard drugs and had been identified as having a cancer that thrived on the mutant ALK protein, were given crizotinib. In 47 cases the tumors shrank – in one they disappeared altogether. In 27 patients the cancer stopped growing.
The authors inform that approximately 5% of NSCLC patients have the type that thrives on the ALK protein.
Geoffrey Shapiro said that even extremely targeted medications, such as crizotinib are vulnerable to resistance from tumors. Co-author Pasi Jänne, MD, PhD studied some of the tumors that had developed resistance and had been surgically removed. The study, published in Cancer Research identified a second mutation in ALK in the patient’s tumor which conferred crizotinib resistance.
“Crizotinib in ALK-Rearranged Inflammatory Myofibroblastic Tumor”
James E. Butrynski, M.D., David R. D’Adamo, M.D., Ph.D., Jason L. Hornick, M.D., Ph.D., Paola Dal Cin, Ph.D., Cristina R. Antonescu, M.D., Suresh C. Jhanwar, Ph.D., Marc Ladanyi, M.D., Marzia Capelletti, Ph.D., Scott J. Rodig, M.D., Ph.D., Nikhil Ramaiya, M.D., Eunice L. Kwak, M.D., Jeffrey W. Clark, M.D., Keith D. Wilner, Ph.D., James G. Christensen, Ph.D., Pasi A. Jänne, M.D., Ph.D., Robert G. Maki, M.D., Ph.D., George D. Demetri, M.D., and Geoffrey I. Shapiro, M.D., Ph.D.
N Engl J Med 2010; 363:1727-1733
“Anaplastic Lymphoma Kinase Inhibition in Non-Small-Cell Lung Cancer”
Eunice L. Kwak, M.D., Ph.D., Yung-Jue Bang, M.D., Ph.D., D. Ross Camidge, M.D., Ph.D., Alice T. Shaw, M.D., Ph.D., Benjamin Solomon, M.B., B.S., Ph.D., Robert G. Maki, M.D., Ph.D., Sai-Hong I. Ou, M.D., Ph.D., Bruce J. Dezube, M.D., Pasi A. Jänne, M.D., Ph.D., Daniel B. Costa, M.D., Ph.D., Marileila Varella-Garcia, Ph.D., Woo-Ho Kim, M.D., Thomas J. Lynch, M.D., Panos Fidias, M.D., Hannah Stubbs, M.S., Jeffrey A. Engelman, M.D., Ph.D., Lecia V. Sequist, M.D., M.P.H., WeiWei Tan, Ph.D., Leena Gandhi, M.D., Ph.D., Mari Mino-Kenudson, M.D., Greg C. Wei, Ph.D., S. Martin Shreeve, M.D., Ph.D., Mark J. Ratain, M.D., Jeffrey Settleman, Ph.D., James G. Christensen, Ph.D., Daniel A. Haber, M.D., Ph.D., Keith Wilner, Ph.D., Ravi Salgia, M.D., Ph.D., Geoffrey I. Shapiro, M.D., Ph.D., Jeffrey W. Clark, M.D., and A. John Iafrate, M.D., Ph.D.
N Engl J Med 2010; 363:1693-1703
Written by Christian Nordqvist