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Brighter future for children with T-ALL
Newsdesk “Trojan horse” strategy enters phase I trial for breast cancer
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even at 100 times the doses we plan to give to patients.” The phase I trial at the University of Toronto’s Princess Margaret Hospital will test five different dose concentrations in 15 patients (three patients to a group) over 12 to 18 months. In addition, notes Reilly, “an advantage of this type of treatment is that it was originally developed as an imaging agent. So in the trial, we’ll not
only assess the safety and toxicity of the agent, as well as any potential response, but we’ll also be looking at tumour uptake and normal tissue uptake using nuclear medicine imaging techniques.” If the treatment works, speculates Reilly, it might also be tried in other epithelial tumours such as ovarian, colorectal, head and neck, squamouscell lung cancer, and glioblastoma. Marilynn Larkin
Brighter future for children with T-ALL “T-cell acute lymphoblastic leukaemia relapse, and central nervous system (T-ALL) can be as treatable as other relapse (J Clin Oncol 2003; 21: forms of paediatric ALL”, says Barbara 3616–22). When these children Asselin (University of Rochester relapse, says Asselin, “we don't do Medical Center, NY, USA) comment- very well at getting their disease back ing on results she and colleagues under control”. obtained as part of the Dana-Farber “This is a cogent summary of the Cancer Institute’s (DFCI; MA, USA) consistently excellent outcomes acute lymphoblastic leukaemia con- obtained for children and adolescents sortium. “We now need to find ways with T-ALL by the DFCI ALL to tailor treatment more specifically to individual patients Rights were not granted so that we can give the most to include this image in aggressive therapies only to those that need them”, she adds. electronic media. Please 10–15% of cases of childrefer to the printed hood ALL involve T-lymphocyte journal. proliferation and, historically, these cancers have been viewed as extremely difficult to treat. “In 1975, cure rates were pretty dismal for all types of ALL and T-ALL is as treatable as other forms of leukaemia. we did not even recognise T-ALL as a separate form of leuk- consortium over the past 15 years”, aemia”, explains Asselin. “By 1985, comments Paul Gaynon (Children's we had developed some effective Hospital, Los Angeles, CA, USA). Like treatments for common ALL but not Asselin, Gaynon believes that further T-ALL and the gap between cure rates improvements in survival will rely for these two types of ALL widened.” on identifying the children most In 1981, the DFCI ALL consor- likely to relapse. In vitro assays of tium started to treat children with responses to drugs, PCR assays for T-ALL in the high-risk group of its minimal residual disease, and treatment protocols. Asselin and co- expression profiling of tumours may workers report that for patients in help to do this, say both researchers. trials done between 1981 and 1995 In addition, more extensive use of the 5-year event-free survival rate for methotrexate, replacement of T-ALL was 75%, which was not sig- prednisone with dexamethasone, and nificantly different from that for inclusion of arabinosylguanine (Arapatients with B-progenitor ALL. G) in treatment regimens should However, patients with T-ALL had a improve results further. higher rate of induction failure, early Jane Bradbury
© Science Photo Library
A drug that pairs a radioactive isotope (indium-111) with epidermal growth factor (EGF), entered phase I trials last month in patients with advanced, chemotherapy-resistant breast cancer. The radiopharmaceutical (111In-hEGF) was developed by Raymond Reilly of the University of Toronto, Canada, and colleagues, who showed that the treatment significantly slowed the growth of large tumours in mice and caused very small, non-established tumours to regress (J Nucl Med 2003; 44: 1469–78). “We exploit the natural internalisation pathway of EGF, which, like a Trojan horse carrying soldiers within it, brings the indium-111 within striking distance of the breast cancer cell nucleus”, explains Reilly. Indium-111 is a low-energy, shortwave electron that has a very short range in tissues, only a few nanometers to a few micrometres; therefore, it cannot harm a cancer cell from the outside or even on the cell surface. “The key”, he says, “is getting it into the cancer cell, where its radioactive particles can destroy the cell’s DNA.” That’s where EGF comes in. EGF binds to receptors on epithelial cells to stimulate their growth, and ultimately is internalised by the cells. Working on the theory that EGF could carry other substances with it, the team combined EGF with the radioactive indium. When breast cancer cells internalised EGF, they also internalised the lethal indium-111. Breast cancer cells are particularly susceptible to the novel radiopharmaceutical because EGF expression is upregulated—up to 100-times higher than in normal epithelial cells— and “it’s that differential that allows us to exploit this idea for treatment of breast cancer”, says Reilly. “Moreover, the major dose-limiting toxicity for cancer treatment is toxicity against bone-marrow stem cells, and those cells are not reported to express EGF receptors.” Furthermore, although liver and kidney cells have moderate concentrations of EGF receptors, “in several of our studies, we’ve specifically examined this and have not found any major toxicity against those organs,
THE LANCET Oncology Vol 4 November 2003
http://oncology.thelancet.com
For personal use. Only reproduce with permission from The Lancet.
650
even at 100 times the doses we plan to give to patients.” The phase I trial at the University of Toronto’s Princess Margaret Hospital will test five different dose concentrations in 15 patients (three patients to a group) over 12 to 18 months. In addition, notes Reilly, “an advantage of this type of treatment is that it was originally developed as an imaging agent. So in the trial, we’ll not
only assess the safety and toxicity of the agent, as well as any potential response, but we’ll also be looking at tumour uptake and normal tissue uptake using nuclear medicine imaging techniques.” If the treatment works, speculates Reilly, it might also be tried in other epithelial tumours such as ovarian, colorectal, head and neck, squamouscell lung cancer, and glioblastoma. Marilynn Larkin
Brighter future for children with T-ALL “T-cell acute lymphoblastic leukaemia relapse, and central nervous system (T-ALL) can be as treatable as other relapse (J Clin Oncol 2003; 21: forms of paediatric ALL”, says Barbara 3616–22). When these children Asselin (University of Rochester relapse, says Asselin, “we don't do Medical Center, NY, USA) comment- very well at getting their disease back ing on results she and colleagues under control”. obtained as part of the Dana-Farber “This is a cogent summary of the Cancer Institute’s (DFCI; MA, USA) consistently excellent outcomes acute lymphoblastic leukaemia con- obtained for children and adolescents sortium. “We now need to find ways with T-ALL by the DFCI ALL to tailor treatment more specifically to individual patients Rights were not granted so that we can give the most to include this image in aggressive therapies only to those that need them”, she adds. electronic media. Please 10–15% of cases of childrefer to the printed hood ALL involve T-lymphocyte journal. proliferation and, historically, these cancers have been viewed as extremely difficult to treat. “In 1975, cure rates were pretty dismal for all types of ALL and T-ALL is as treatable as other forms of leukaemia. we did not even recognise T-ALL as a separate form of leuk- consortium over the past 15 years”, aemia”, explains Asselin. “By 1985, comments Paul Gaynon (Children's we had developed some effective Hospital, Los Angeles, CA, USA). Like treatments for common ALL but not Asselin, Gaynon believes that further T-ALL and the gap between cure rates improvements in survival will rely for these two types of ALL widened.” on identifying the children most In 1981, the DFCI ALL consor- likely to relapse. In vitro assays of tium started to treat children with responses to drugs, PCR assays for T-ALL in the high-risk group of its minimal residual disease, and treatment protocols. Asselin and co- expression profiling of tumours may workers report that for patients in help to do this, say both researchers. trials done between 1981 and 1995 In addition, more extensive use of the 5-year event-free survival rate for methotrexate, replacement of T-ALL was 75%, which was not sig- prednisone with dexamethasone, and nificantly different from that for inclusion of arabinosylguanine (Arapatients with B-progenitor ALL. G) in treatment regimens should However, patients with T-ALL had a improve results further. higher rate of induction failure, early Jane Bradbury
© Science Photo Library
A drug that pairs a radioactive isotope (indium-111) with epidermal growth factor (EGF), entered phase I trials last month in patients with advanced, chemotherapy-resistant breast cancer. The radiopharmaceutical (111In-hEGF) was developed by Raymond Reilly of the University of Toronto, Canada, and colleagues, who showed that the treatment significantly slowed the growth of large tumours in mice and caused very small, non-established tumours to regress (J Nucl Med 2003; 44: 1469–78). “We exploit the natural internalisation pathway of EGF, which, like a Trojan horse carrying soldiers within it, brings the indium-111 within striking distance of the breast cancer cell nucleus”, explains Reilly. Indium-111 is a low-energy, shortwave electron that has a very short range in tissues, only a few nanometers to a few micrometres; therefore, it cannot harm a cancer cell from the outside or even on the cell surface. “The key”, he says, “is getting it into the cancer cell, where its radioactive particles can destroy the cell’s DNA.” That’s where EGF comes in. EGF binds to receptors on epithelial cells to stimulate their growth, and ultimately is internalised by the cells. Working on the theory that EGF could carry other substances with it, the team combined EGF with the radioactive indium. When breast cancer cells internalised EGF, they also internalised the lethal indium-111. Breast cancer cells are particularly susceptible to the novel radiopharmaceutical because EGF expression is upregulated—up to 100-times higher than in normal epithelial cells— and “it’s that differential that allows us to exploit this idea for treatment of breast cancer”, says Reilly. “Moreover, the major dose-limiting toxicity for cancer treatment is toxicity against bone-marrow stem cells, and those cells are not reported to express EGF receptors.” Furthermore, although liver and kidney cells have moderate concentrations of EGF receptors, “in several of our studies, we’ve specifically examined this and have not found any major toxicity against those organs,
THE LANCET Oncology Vol 4 November 2003
http://oncology.thelancet.com
For personal use. Only reproduce with permission from The Lancet.