Chasing Small Cell Lung Cancer
Small cell lung cancer (SCLC) is a carcinoma, meaning it is invasive and arises from the epithelial cells lining the lungs. Like other cancers, it is associated with proto-oncogene activation and the loss of tumour-suppressor genes, both of which are responsible for ensuring normal cell function. In addition, SCLC can evade apoptosis (a form of cell death induced by many cancer therapies), which causes limitations in treatment. Lung cancer more broadly is among the most commonly diagnosed cancers worldwide and causes over 1.5 million deaths per year. It is commonest in the elderly and those with a history of smoking. It frequently spreads to other organs such as the liver, and less than 5% of patients survive longer than five years.
STATUS QUO OF SCLC TREATMENT
Currently, SCLC is treated using chemotherapy and radiotherapy which induce DNA damage in the cancer cells. Both radiotherapy and chemotherapy, although effective at inducing damage, can also damage healthy tissues. Pairing these treatments with DNA repair inhibitors can enhance tumour growth reduction. Accordingly, SCLC patients are commonly treated with radiotherapy and cisplatin chemotherapy combined with a DNA repair inhibitor, etoposide. However, SCLC can develop resistance to these standard treatments, related to their intra-tumoural heterogeneity. Intra-tumoural heterogeneity describes the variation found in gene expression and behaviour between tumour cells within a single tumour. This heterogeneity means that a small proportion of tumour cells may be resistant to a given treatment, allowing the tumour to regrow even if most tumour cells are killed. More research into the molecular biology of SCLC is required to assess how more effective novel treatments can be created.
There have been various attempts to improve SCLC treatment. Recently, the use of rovalpituzumab, an antibody-drug conjugate, was explored. The antibody component binds to DLL3, which is found on the surface of SCLC cells and is implicated in accelerating SCLC tumour growth. This targets the attached drug to tumour cells, where it causes DNA damage (Furuta et al., 2019). However, in clinical trials it was less effective than standard treatments (Blackhall et al., 2021). In lung cancers, cells may have a mutation in their epidermal growth factor receptor (EGFR), which is a protein involved in regulating the growth and division of a cell. Identifying this gene allows treatment with drugs inhibiting EGFR (e.g. gefitinib), allowing a tailored approach to destroying the tumour. Unfortunately, only a small proportion of SCLC harbour this mutation.
A ROLE FOR BIOMARKERS
The identification of four major subtypes of SCLC has presented potential new treatments. Each subtype has a different sensitivity to different inhibitors and a distinctive gene expression pattern (Gay et al., 2021). One approach to identify the SCLC subtype prior to treatment is the use of biomarker profiling, either by taking a biopsy of the solid tumour or a blood test. Identifying these patterns and classifying the subtype of SCLC through biomarkers, allows selection of the correct inhibitor, making treatment more effective.
Exome and genome sequencing have been used to identify new drug targets such as mutations in the PI3K gene which are involved in the uncontrolled growth of cancer cells. Sequencing can also allow biomarker prediction, which can then be used to select the appropriate course of treatment to avoid drug resistance. The use of biomarkers is being further investigated to incorporate the use of liquid biopsies, which sample cancer cells and DNA circulating in the blood. This allows monitoring of intra-tumoral heterogeneity, presenting the possibility of switching treatments to avoid resistance. Moreover, the use of biomarkers will allow patients to be placed in clinical trials as appropriate, according to their genes rather than the location of their tumours, which is not always relevant to tumour cell gene expression or behaviour. These factors in combination would support better treatment results (Frese et al., 2021).
Research regarding SCLC is now focussing on the use of biomarker testing to identify the subtype of SCLC, which will allow a more personalised treatment plan to be put into place for patients. This adjustment aims to deliver the correct therapeutics, minimising issues such as drug resistance.
Blackhall, F., Jao, K., Greillier, L., Cho, B.C., Penkov, K., Reguart, N., Majem, M., Nackaerts, K., Syrigos, K., Hansen, K. and Schuette, W. 2021. Efficacy and safety of rovalpituzumab tesirine compared with topotecan as second-line therapy in DLL3-high SCLC, Journal of Thoracic Oncology, 19(9), pp. 1547-1558. https://doi.org/10.1016/j.jtho.2021.02.009.
Frese, K.K., Simpson, K.L. and Dive, C., 2021. Small cell lung cancer enters the era of precision medicine, Cancer Cell, 39(3), pp. 297-299. 10.1016/j.ccell.2021.02.002.
Furuta, M., Kikuchi, H., Shoji, T., Takashima, Y., Kikuchi, E., Kikuchi, J., Kinoshita, I., Dosaka‐Akita, H. and Sakakibara‐Konishi, J., 2019. DLL 3 regulates the migration and invasion of small cell lung cancer by modulating Snail, Cancer Science, 110(5), pp.1599-1608. 10.1111/cas.13997.
Gay, C.M., Stewart, C.A., Park, E.M., Diao, L., Groves, S.M., Heeke, S., Nabet, B.Y., Fujimoto, J., Solis, L.M., Lu, W. and Xi, Y., 2021. Patterns of transcription factor programs and immune pathway activation define four major subtypes of SCLC with distinct therapeutic vulnerabilities, Cancer Cell, 39(3), pp. 246-360. 2021. 10.1016/j.ccell.2020.12.014.