Despite the recent progress in treatment options, lung cancer remains a leading cause of global cancer-related death. It estimates approximately two million new cases for 2020. The prognosis for lung cancer patients is generally poor, with an overall five-year survival rate of roughly 15%. 

Two principal clinical categories of lung cancer can be distinguished: small cell lung carcinoma (SCLC) representing 15% of lung cancers, and non-small-cell lung carcinoma (NSCLC) which accounts for about 85% of all lung carcinomas (derived from bronchial epithelial cells).

NSCLC includes the most common forms: adenocarcinomas, squamous cell carcinomas, and large cell carcinomas. SCLC proliferates more rapidly than NSCLC but responds more efficiently toward chemotherapy.

The four stages of lung tumor progression

The localization of the tumor determines lung tumor staging, that is whether it remains locally within the lungs or if tumor cells have disseminated from the lungs towards the lymph nodes or any other organs.

Stage I: The tumor is restricted to the lungs and shows no spread to any lymph nodes.

Stage II: The tumor remains within the lungs and proximal lymph nodes.

Stage III: The tumor is found within the lungs and in the lymph nodes in the middle of the chest.

Stage IV: The tumors show they spread to both lungs, the pleural tissue surrounding the lungs, or more distal areas, such as the liver and other organs.

Since the lungs are large organs, early stages of lung tumor development (such as stage I/II) are challenging to detect.

Recent advances to treat NSCLC: targeted therapy

Available anti-lung cancer therapy treatments, like most other onco-therapies, also negatively affect the viability of healthy untransformed cells, causing unwanted side effects. The rapidly evolving and novel field of targeted anti-tumor therapies has become tailored to be more specific and more efficient in eradicating tumor cells and also radically reducing the damage to normal parental tissue.

The therapy of choice for each patient is mainly based on tumor histopathology and molecular parameters such as the presence or absence of key genetic alterations. Clinical treatments for NSCLC include surgery, chemotherapy, radiotherapy, targeted drug therapy, and, recently, immunotherapy.

Standard chemotherapy has been the primary treatment option in NSCLC, but unfortunately, it is often associated with limited efficacy and overall poor patient survival. Further, since most lung cancer patients are diagnosed with advanced disease (stage III/IV), these treatments are unlikely to result in complete cures, but may however significantly improve survival and provide symptom relief.

Targeted drug therapy differs from traditional chemotherapy, which also uses drugs to treat cancer. Targeted therapies work principally by targeting specific genes, proteins, and epigenetic marks that negatively affect tumor growth and survival.

Several anti-cancer drugs targeting different proteins, undergoing clinical trials, have been developed. According to the Food and Drug Administration (FDA), there are 64 drugs approved for NSCLC and 18 drugs approved for SCLC. As a result of treatments becoming more efficient and more personalized, survival for selected groups of NSCLC patients is increasing. 

Attractive therapeutic targets to treat lung cancers 

The currently used targeting treatment of NSCLC in the clinic includes, among others, inhibition of targets, involved in many aspects of cancer growth and tumor blood vessel formation (angiogenesis), thus slowing cancer progression.

These therapies target several receptors signaling pathways like the epidermal growth factor receptor (EGFR), anaplastic lymphoma kinase (ALK), phosphatidylinositol 3-kinase (PI3Ks), mechanistic Target Of Rapamycin (mTOR), Human Epidermal growth factor Receptor-2 (HER2), Vascular Epidermal Growth Factor Receptor (VEGFR), Kirsten Human Rat Sarcoma protein (KRAS), hepatocyte growth factor receptor (c-MET), and v-Raf murine sarcoma viral oncogene homolog B (BRAF).

Let us take a brief look at a standard (EGFR) and a promising (PI3K) therapeutic target for NSCLC.

EGFR: a standard in the treatment of NSCLC patients

The epidermal growth factor receptor, EGFR, is an oncogene product that drives NSCLC tumor progression. Although the prognostic value of EGFR as a marker for lung cancer is still unclear, EGFR mutations are found in lung tumors in 10–15% of Caucasian patients and 30–40% of East Asia patients. EGFR mutations promote tumorigenesis by increasing tumor cell proliferation, angiogenesis, and metastasis.

The development and clinical application of EGFR inhibitors provides essential insights for new lung cancer therapies. Although associated with severe adverse events, the tyrosine kinase inhibitors approved for NSCLC therapy, such as Gefitinib, Erlotinib, Afatinib, and Osimertinib, are now considered the standard in the first-line treatment of NSCLC patients carrying the EGFR-mutation.

PI3K: a promising target for NSCLC therapy.

Many studies show a 50-70% overexpression of phosphorylated Akt in NSCLC, indicating that abnormal activation of the phosphatidylinositol-3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) pathway is a frequent event. PI3K-Akt-mTOR signaling pathway remains one of the most critical intracellular pathways and a master regulator of tumorigenesis. Activation of the PI3K pathway contributes to the development of tumors, and PI3K is particularly hyper-activated in lung cancer, where it regulates a broad range of cellular processes, including proliferation, survival, angiogenesis, and metastasis. 

Hence, inhibition of PI3K signaling is an attractive way to treat NSCLC and several other tumor types.

Although PI3K inhibitors evidently inhibit NSCLC tumor progression,  PI3K inhibitors have yet to be approved for lung cancer therapy. Several phases I and phase II clinical trials targeting PI3K in NSCLC are currently ongoing. These are either tested alone (monotherapy) or in a cocktail (combination) with a cytotoxic chemotherapeutic or a standard NSCLC treatment, like Erlotinib.

The PI3K-Akt-mTOR signaling pathway is the target of many novel inhibitors. Drugs candidate targeting PI3K in clinical trials act via different mechanisms, all resulting in the reduction of cellular proliferation and an increase in cellular death. They are mainly categorized as 1) dual PI3K/mTOR inhibitors, 2) Pan-PI3K inhibitors, 3) Isoform-specific PI3K inhibitors.

Obtaining the maximal benefits and minimal adverse effects from these targeted therapies while identifying predictive companion disease biomarkers, is paramount for patients. Incorporating biomarker analysis and patient enrichment strategies in clinical trials is, in fact, essential in translational lung cancer research.

Readings

Dong C. et al. The antipsychotic agent flupentixol is a new PI3K inhibitor and potential anticancer drug for lung cancer. Int J Biol Sci 2019; 15(7):1523-1532

Jing Yang et al. Targeting PI3K in cancer: mechanisms and advances in clinical trials. Molecular Cancer (2019) 18: 26

Po Yee Yip. Phosphatidylinositol 3-kinase-AKT-mammalian target of rapamycin (PI3K-Akt-mTOR) signaling pathway in non-small cell lung cancer.  TLCR Translational Lung Cancer Research (2015); 4:2

Shtivelman E. et al. Molecular pathways and therapeutic targets in lung cancer. Oncotarget 2014 5(6): 1392–1433.