Tumor heterogeneity dictates sensitivity to gefitinib (Iressa(TM)/ZD1839) in solid tumor models

The epidermal growth factor receptor (EGFR) and its ligands are overexpressed in many human tumors, including bladder and pancreas, correlating with a more aggressive tumor phenotype and poor patient prognosis. We initiated the present study to characterize the heterogeneity of gefitinib responsiveness in a panel of human bladder and pancreatic cancer cell lines in order to identify the biological characteristics of EGFR-dependent proliferation that could be used to prospectively identify drug-sensitive tumors. A second objective was to elucidate how to best exploit these results by utilizing gefitinib in combination therapy. To these ends, we examined the effects of the EGFR antagonist gefitinib on proliferation and apoptosis in a panel of 18 human bladder cancer cell lines and 9 human pancreatic cancer cell lines. Our data confirmed the existence of marked heterogeneity in Iressa responsiveness with less than half of the cell lines displaying significant growth inhibition by clinically relevant concentrations of the drug. Gefitinib responsiveness was found to be p27 kip1 dependent as DNA synthesis was restored following exposure to p27siRNA. Unfortunately, Iressa responsiveness was not closely linked to surface EGFR or TGF-α expression in the bladder cancer cells, however, cellular TGF-α expression correlated directly with Iressa sensitivity in the pancreatic cancer cell lines. These findings provide the potential for prospectively identifying patients with drug-sensitive tumors. ^ Further studies aimed at exploiting gefitinib-mediated cell cycle effects led us to investigate if gefitinib-mediated TRAIL sensitization correlated with increased p27kip1 accumulation. We observed that increased TRAIL sensitivity following gefitinib exposure was not dependent on p27 kip1 expression. Additional studies initiated to examine the role(s) of Akt and Erk signaling demonstrated that exposure to PI3K or MEK inhibitors significantly enhanced TRAIL-induced apoptosis at concentrations that block target phosphorylation. Furthermore, combinations of TRAIL and the PI3K or MEK inhibitors increased procaspase-8 processing above levels observed with TRAIL alone, indicating that the effects were exerted at the level of caspase-8 activation, considered the earliest step in the TRAIL pathway. ^

MS#73 William C. Moloney, M.D., papers; 1952-1954

Dr. Moloney kept a personal journal, with photographs, for much of his two years with the Atomic Bomb Casualty Commission in Japan. Along with other scientists, he studied the biological and medical effects of ionized radiation on the survivors of the Hiroshima and Nagasaki atomic bombings. In January of 1986, Dr. Moloney donated his journal, correspondence and diary pages to the Harris County Medical Archive, whose collections were later incorporated into the Texas Medical Center Library. Dr. Moloney's journal is in relatively good shape containing a mix of handwritten notes and comments, news-clippings, photos, and ephemera. The journal is an important record of personal impressions, thoughts and details of events during a pivotal time in Japan. This 192-pagee journal gives new insights into the work of the ABCC and into the people who participated in that work. The journal covers the period from April 1952 to February 1954. In these documents, Moloney records his struggles with understanding the Japanese culture, his frustration at not being allowed to treat the survivors he studied, and his concerns, fears, hopes and revelations as he dealt with the bombing survivors and their children. The original papers are open for research at the John P. McGovern Historical Collections and Research Center in the TMC Library in Houston.