MI

Lung cancer is the leading cause of cancer related death among women and men and the second most diagnosed cancer in the world, causing 1.8 million deaths annually. Surgical resection of the primary tumor is the standard of care whenever possible. However, 90% of lung cancer deaths are caused by metastases months-to-years after surgery. Current screening tools such as high-resolution Computed Tomography (CT) and Positron Emission Tomography (PET) can only identify tumors that have reached a detectable size, that often correlates with advanced disease. However, this technology carries side problems, including the false positive rate that led to follow-up tests and invasive procedures that confers additional risks to patients.  

Therapeutic strategies targeting specific driver mutations have emerged in recent years for the treatment of metastatic non-small cell lung cancer and have improved survival, yet the initial identification of these molecular alterations depends on biopsies of metastatic lesions after the resection of the primary tumor. For biopsy, the metastatic lesion must be large enough to be detectable by clinical imaging tools, and this large lesion indicates a relatively advanced stage of disease. Biopsy of these lesions is often difficult from both location and patient-safety perspective. An emerging option is a blood draw or liquid biopsy to obtain circulation tumor DNA (ctDNA) for mutation analyses, yet the ctDNA is not abundant in circulation until relatively large metastases have already formed.  

Therefore, novel, efficient, and affordable approaches are needed for disease surveillance. We propose a high sensitive, minimally-invasive and efficient cell capture device for easy isolation of tumor cells at early stages of disease, whose analysis can identify targeted therapeutics that can be applied while the disease burden and heterogeneity are low. Furthermore, this technology would increase the coverage of the eligible population and reduce the clinical costs by using histopathology analysis of the sentinel implant. This device is a porous biomaterial scaffold that, when implanted, is vascularized, and infiltrated by immune cells and subsequently cancer cells, acting as a synthetic sentinel niche that provides information about the disease development and progression. Our previous studies in breast and pancreatic cancer models have demonstrated that tumor cells are detectable early after tumor initiation and during the progression of the disease. A comparative analysis of scaffolds and ctDNA showed that the implant captured and therefore detected cancer cells before positive detection of ctDNA.  

We will determine the genomic and transcriptomic prolife of inoculated lung cancer cells in PDX’s murine model at early time points. We anticipate that the tumor cells captured by the scaffolds will recapitulate the genotype of the parental PDX. The scaffold safety will be investigated in a Phase I clinical study of metastatic lung cancer patients implanted with our scaffold, with biopsy and subsequent removal to analyze captured cells. Sequencing analysis will be applied to captured cancer cells to assess their genomic and transcriptomic profile. We foresee the use of these bioengineered implants for surveillance in high-risk lung cancer patients, with analysis of the collected cells employed to identify personalized therapeutic strategies to improve patient outcome.

Lorlatinib is currently the only approved ALK TKI (tyrosine kinase inhibitor) for patients with ALK NSCLC that have progressed on prior lines of therapy. The clinical benefit of lorlatinib is modest in previously-treated patients with a median PFS of 7 months (1). Mechanisms of lorlatinib resistance are diverse and include novel ALK mutations, compound ALK mutations, and activation of bypass pathways including AXL. Gilteritinib is a dual inhibitor of FLT3/AXL that is approved for relapsed/refractory FLT3+ acute myeloid leukemia (AML). Pre-clinical work using ALK fusion positive cell lines (including those containing compound mutations), patient-derived tumor cells, and in vivo mouse studies all demonstrate the anti-tumor activity of gilteritinib specifically against lorlatinib-resistant ALK NSCLC.

We will recruit patients with ALK NSCLC with progression on lorlatinib and collect patient-derived tumor samples. In addition to surgical, biopsy, or effusion fluid samples, plasma will be collected for isolation of circulating tumor DNA and circulating tumor cells. Whole exome sequencing (WES) will be used to identify molecular alterations that define resistance mechanisms. Ex vivo drug testing will be conducted using our existing platform and will include ALK inhibitors and inhibitors of pathways implicated in resistance such as AXL, MET, mTOR, and MAPK. Results of ex vivo drug testing will be correlated with findings from WES.

Simultaneously, we will open a phase I clinical trial to assess the safety and preliminary efficacy of gilteritinib in patients with lorlatinib-resistant ALK NSCLC. Crucially, clinical endpoints will be correlated with sequencing data and ex vivo drug testing results.