Elsevier

Seminars in Oncology

Volume 31, Supplement 1, February 2004, Pages 106-111
Seminars in Oncology

Targeted molecules in small cell lung cancer

https://doi.org/10.1053/j.seminoncol.2003.12.021Get rights and content

Abstract

Because small cell lung cancer is decreasing in frequency in North America, the tempo of clinical trials in general and investigation of molecular-targeted therapy is less active than for non-small cell lung cancer. Nevertheless, progress in the understanding of the molecular pathogenesis of small cell lung cancer has been substantial. Potentially relevant molecular targets have been identified and drugs have been developed to exploit them. This article discusses the common expression of c-Kit receptor tyrosine kinases in small cell lung cancer and its potential to serve as an effective target for small-molecule inhibitors such as imatinib mesylate. Another innovation described is the development of an immunoconjugate (BB-10901) that links an antibody targeting the CD56 antigen of the neural cell adhesion molecule family with a potent maytansinoid cytotoxic component. These novel strategies are currently in clinical trials and potentially will allow additional therapeutic options for patients resistant to conventional strategies. Should these proof-of-concept studies show promise, integration of these agents with conventional modalities in previously untreated patients will follow.

Section snippets

c-Kit inhibition in small cell lung cancer

Certain receptor tyrosine kinases (RTKs) are overexpressed in SCLC. The RTKs contain an N-terminal extracellular binding domain, a single transmembrane helix, and a cytosolic C-terminal domain with tyrosine kinase activity. Some RTKs are proto-oncogenes involved in alterations of reactive oxygen species; activation of downstream signal-transduction molecules; and cellular proliferation, migration, and survival, all key events in metastasis.4 Accordingly, inhibition of RTKs may be effective

Development of the immunoconjugate BB-10901 (huN901-DM1) for small cell lung cancer

BB-10901 (huN901-DM1) is an immunoconjugate tumor-activated prodrug under development for the treatment of SCLC and other neuroendocrine malignancies. A tumor-activated prodrug is a conjugate of a cytotoxin bound to an antibody. The cytotoxic component of the complex is inactive until it reaches its target site. At the target site, the conjugate binds to the tumor cell and is internalized to release the cytotoxin intracellularly. BB-10901 is an immunoconjugate consisting of the humanized

Investigation of BB-10901 for relapsed and refractory small cell lung cancer

We are conducting an ongoing phase I trial of BB-10901 for SCLC and other neuroendocrine malignancies.20 Eligible patients have SCLC that is either relapsed or refractory to prior chemotherapy. We are also enrolling patients with extrapulmonary small cell cancers and other neuroendocrine tumors, provided that CD56 positivity is confirmed. Eligible patients may have had no more than three prior chemotherapy regimens. Because of the possibility of neurotoxicity with the drug, patients with a

Conclusions

As the understanding of the molecular basis of SCLC increases, changes in the natural history of this cancer become possible with treatments using a combination of cytotoxic chemotherapy and target-specific drugs. Tailoring therapy based on genetic or protein expression profiles of individual tumors is likely to be a requirement in this anaplastic tumor. Disruption of signal-transduction pathways such as the c-Kit autocrine loop with a tyrosine kinase inhibitor and creation of an

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1

Dr Murray has received honoraria and served as a consultant to AstraZeneca Pharmaceuticals, LP, and Aventis Oncology. Dr Fossella has received research grant support from British Biotech.

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