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KIT not the only determinant for GISTs
Newsdesk KIT not the only determinant for GISTs that GIST diagnosis cannot exclusively rely on the presence of KIT and it emphasises that tyrosine kinase mutations promoting tumorigenesis can exist in previously unsuspected situations in both leukemias and solid tumours. “Because kinases are excellent pharmacologic targets, cancers with mutant kinases might be effectively treated with kinase inhibitors”, he says. “This is a landmark paper”, says Carl-Henrik Heldin (Ludwig Institute for Cancer Research, Uppsala, Sweden), “because it could lead to the identification of a subset of patients Courtesy of M Heinrich
Patients with gastrointestinal stromal tumours (GISTs) who do not have mutations in the KIT-receptor tyrosine kinase may have intragenic activation mutations in a related receptor tyrosine kinase called platelet-derived growthfactor-receptor-alpha (PDGFR␣), according to a new study.
Comparison of KIT immunohistochemistry in 3 GISTs with KIT mutation (a, b, d) and 1 GIST with PDGFR␣ mutation (c).
“PDGFR␣ is found in many body tissues, so it also will be important to determine whether mutations in this enzyme might play a role in other cancers”, explains lead author Michael Heinrich (Oregon Health and Science University, USA). More than 85% of patients with GISTs have mutations in the KIT-receptor tyrosine kinase and the presence of KIT is generally considered an important factor for the diagnosis of GIST or for the selection of patients suitable for Imatinib therapy. Heinrich and colleagues detected PDGFR␣ mutations in 14 out of 40 GISTs lacking KIT mutations. Both PDGFR␣ and KIT mutations were mutually exclusive events in GISTs (Science 2003; 299: 708–10). “We predict that more human cancers will be identified as being associated with mutant PDGFR␣ and that some of the mutant PDGFR␣ kinases associated with GISTs can be inhibited by Imatinib therapy”, says Heinrich. Charles Sawyers (University of California, Los Angeles, CA, USA) considers the work particularly important because it makes a clear distinction
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who could respond to a specific therapy”. According to Ian Judson (Royal Marsden Hospital, London, UK) this is an important step forward but there is still much to learn about the activity of Imatinib and the biology of GISTs. “It is somewhat puzzling that these particular patients do not respond well to Imatinib in spite of the fact that the agent also inhibits PDGFR␣. Perhaps the mutant form of the receptor is less sensitive to inhibition, something that will clearly need to be explored further”, comments Judson. Khabir Ahmad
New drug enters PDT clinical trials A new photosensitising agent called phthalocyanine 4 (Pc4), which can be used in photodynamic therapy (PDT), has shown good efficacy in preclinical studies and is about to be tested in a phase I clinical trial, US scientists have announced. According to lead researcher Timothy Kinsella (Case Western Reserve University, OH, USA), “if the trial is successful, PDT with Pc4 will eventually join surgery, radiation, and chemotherapy as part of the arsenal against cancer”. Currently, only porfimer sodium (Photofrin) has received approval from the US Food and Drug Administration for use as a photosensitiser in PDT. This treatment is used for certain patients with a partially or completely obstructive oesophageal cancer or an obstructive endobronchial non-small-cell lung carcinoma. “The disadvantages to [porfimer sodium] are that it is far from optimal in terms of preferential retention in the tumour compared to normal tissues”, explains Eli Glatstein, University of Pennsylvania, USA. “Patients [given porfimer sodium] must also limit their exposure to sunlight for four to six weeks to prevent serious skin reactions from environmental exposure,” he adds.
According to Glatstein, a pure compound is likely to be cleared from the body much more rapidly. Pc4 is a single molecule that accumulates in the mitochondria and is structurally similar to porphyrin. By comparison, porfimer sodium is a complex compound made up of a mixture of oligomers formed by ether and ester linkages to porphyrin units. “As I recall, the preclinical data [for Pc4] are quite good”, notes an expert in the field. “The main theoretical advantage is that Pc4 is activated at a wavelength [that penetrates tissue more deeply] than [porfimer sodium].” According to Kinsella and colleagues, the mechanisms underlying Pc4 are still being identified, but when used with PDT, it strongly induces apoptosis. The researchers also point out that tumours respond “very rapidly”, with “a high incidence of apoptosis in the early hours after a single treatment and [a] complete loss of visible tumour [is seen witihn] a few days”. The planned phase I trial will evaluate patients with cutaneous skin lesions that have metastasised from various cancers such as lymphoma, non-melanoma skin cancers, breast cancer, and head and neck carcinoma. Emma Hitt
THE LANCET Oncology Vol 4 March 2003
http://oncology.thelancet.com
For personal use. Only reproduce with permission from The Lancet Publishing Group.
Patients with gastrointestinal stromal tumours (GISTs) who do not have mutations in the KIT-receptor tyrosine kinase may have intragenic activation mutations in a related receptor tyrosine kinase called platelet-derived growthfactor-receptor-alpha (PDGFR␣), according to a new study.
Comparison of KIT immunohistochemistry in 3 GISTs with KIT mutation (a, b, d) and 1 GIST with PDGFR␣ mutation (c).
“PDGFR␣ is found in many body tissues, so it also will be important to determine whether mutations in this enzyme might play a role in other cancers”, explains lead author Michael Heinrich (Oregon Health and Science University, USA). More than 85% of patients with GISTs have mutations in the KIT-receptor tyrosine kinase and the presence of KIT is generally considered an important factor for the diagnosis of GIST or for the selection of patients suitable for Imatinib therapy. Heinrich and colleagues detected PDGFR␣ mutations in 14 out of 40 GISTs lacking KIT mutations. Both PDGFR␣ and KIT mutations were mutually exclusive events in GISTs (Science 2003; 299: 708–10). “We predict that more human cancers will be identified as being associated with mutant PDGFR␣ and that some of the mutant PDGFR␣ kinases associated with GISTs can be inhibited by Imatinib therapy”, says Heinrich. Charles Sawyers (University of California, Los Angeles, CA, USA) considers the work particularly important because it makes a clear distinction
136
who could respond to a specific therapy”. According to Ian Judson (Royal Marsden Hospital, London, UK) this is an important step forward but there is still much to learn about the activity of Imatinib and the biology of GISTs. “It is somewhat puzzling that these particular patients do not respond well to Imatinib in spite of the fact that the agent also inhibits PDGFR␣. Perhaps the mutant form of the receptor is less sensitive to inhibition, something that will clearly need to be explored further”, comments Judson. Khabir Ahmad
New drug enters PDT clinical trials A new photosensitising agent called phthalocyanine 4 (Pc4), which can be used in photodynamic therapy (PDT), has shown good efficacy in preclinical studies and is about to be tested in a phase I clinical trial, US scientists have announced. According to lead researcher Timothy Kinsella (Case Western Reserve University, OH, USA), “if the trial is successful, PDT with Pc4 will eventually join surgery, radiation, and chemotherapy as part of the arsenal against cancer”. Currently, only porfimer sodium (Photofrin) has received approval from the US Food and Drug Administration for use as a photosensitiser in PDT. This treatment is used for certain patients with a partially or completely obstructive oesophageal cancer or an obstructive endobronchial non-small-cell lung carcinoma. “The disadvantages to [porfimer sodium] are that it is far from optimal in terms of preferential retention in the tumour compared to normal tissues”, explains Eli Glatstein, University of Pennsylvania, USA. “Patients [given porfimer sodium] must also limit their exposure to sunlight for four to six weeks to prevent serious skin reactions from environmental exposure,” he adds.
According to Glatstein, a pure compound is likely to be cleared from the body much more rapidly. Pc4 is a single molecule that accumulates in the mitochondria and is structurally similar to porphyrin. By comparison, porfimer sodium is a complex compound made up of a mixture of oligomers formed by ether and ester linkages to porphyrin units. “As I recall, the preclinical data [for Pc4] are quite good”, notes an expert in the field. “The main theoretical advantage is that Pc4 is activated at a wavelength [that penetrates tissue more deeply] than [porfimer sodium].” According to Kinsella and colleagues, the mechanisms underlying Pc4 are still being identified, but when used with PDT, it strongly induces apoptosis. The researchers also point out that tumours respond “very rapidly”, with “a high incidence of apoptosis in the early hours after a single treatment and [a] complete loss of visible tumour [is seen witihn] a few days”. The planned phase I trial will evaluate patients with cutaneous skin lesions that have metastasised from various cancers such as lymphoma, non-melanoma skin cancers, breast cancer, and head and neck carcinoma. Emma Hitt
THE LANCET Oncology Vol 4 March 2003
http://oncology.thelancet.com
For personal use. Only reproduce with permission from The Lancet Publishing Group.