The first week of April definitely started with a bang! After the 2019 in-person small cell lung cancer (SCLC) meeting—convened by the International Association for the Study of Lung Cancer (IASLC) and hosted by Memorial Sloan Kettering Cancer in New York—the pandemic hit us in 2020. The 2021 meeting was virtual, so it was absolutely amazing to be back in person at the 2023 Small Cell Lung Cancer IASLC Hot Topics Meeting, again at Memorial Sloan Kettering.
This meeting is a testament to all the preclinical scientists and clinicians coming together to tackle what has been a really difficult nut to crack, the early detection and treatment of SCLC. SCLC is a very interesting disease. Identified as a unique form of lung cancer in 1959, SCLC comprises 15% of all diagnosed cases of lung cancer. SCLC responds to initial chemotherapy; however, it inevitably becomes resistant to the chemotherapy and comes back. Also, unlike targetable mutations, such as EGFR and ALK, seen in non-small cell lung cancer (NSCLC), most molecular changes seen in SCLC are seen in genes such as RB1 and TP53 that are difficult to target.
The past decade has seen a huge amount of progress in our understanding of the biology of SCLC and how this is translating into new clinical research.
New Technologies to Detect SCLC Early and Follow the Disease to Monitor Treatment Response
SCLC grows notoriously fast and therefore lung cancer screening through low-density computed tomography (LDCT) may not be adequate to catch the disease. SCLC is unique in that the disease sheds cancer cells (circulating tumor cells or CTCs) or tumor DNA (circulating tumor FNA or ctDNA) into the blood even when the cancer is small in size and may not be detected in an LDCT. Researchers have exploited this property to develop tests that can detect cells or the ctDNA from SCLC early on in the disease. While still in early stages of testing, there is an opportunity to use this technology to develop early detection tools for this fast-growing cancer.
Another property that is unique to SCLC is that these cancer cells can elicit an immune response; that is, B cells from the immune system can produce antibodies against SCLC—also called autoantibodies. These autoantibodies are detectable in the blood quite early and therefore are being used to detect SCLC early.
Also, biopsy tissue is very difficult to obtain in SCLC, and this has hampered progress. However, scientists are now able to capture SCLC CTCs from blood and develop mouse models to study the disease, thus circumventing the issue with tissue.
SCLC Is a Highly Heterogenous Disease Consisting of Highly Plastic Cells
Now that’s quite a mouthful! So let me unpack this a bit more. Currently, both limited-stage SCLC (LS-SCLC) and extensive-stage SCLC (ES-SCLC) are treated as homogeneous diseases: every patient gets the same treatment. In the case of ES-SCLC, patients receive an immunotherapy-chemotherapy combination. However, It is now known that SCLC is a collection of four subtypes—SCLC-A, SCLC-N, SCLC-P, and SCLC-I. The SCLC-I subtype is also known as the Inflamed subtype and is more responsive to immunotherapy. Thus, we know that the disease is in fact heterogenous and that a one-size-fits-all approach won’t benefit patients. Currently, lots of research on how to convert the SCLC-A, SCLC-N, and the SCLC-P subtypes into the inflamed subtype is ongoing. We will also see more patient selection in clinical trials to personalize treatment options.
SCLC cells are also plastic—each cell can change from one cell into another different type based on the treatment. For example, an SCLC-A cell can start behaving like an SCLC-N cell. This property is incredibly important to understand because this plastic nature of SCLC cells leads to their ability to escape therapies. Scientists are hard at work figuring out how to manipulate this plasticity to develop drugs.
New Drugs on the Horizon
Researchers are building upon this basic science knowledge to identify and test new drug targets. Drugs that target the epigenetic pathway proteins, such as EZH2 and LSD1, are currently being studied in preclinical models and phase 1 trials. These epigenetic pathway proteins help SCLC cells escape the effect of chemotherapy or immunotherapy, and combining drugs that target these proteins with chemotherapy or immunotherapy may help sensitize SCLC cells to these drugs. Other drugs that target the DLL3 protein on the surface of SCLC (such as BITES) or drugs that activate the DNA Damage Response pathway may also prove to be interesting from a clinical standpoint, based on preclinical studies.
Where Are We and Where Do We Go From Here
The meeting was concluded by LUNGevity Scientific Advisory Board Chair and professor of Thoracic Oncology, Dr. Charles Rudin. He reminded the community of the importance of funding research into hard-to-treat diseases such as SCLC. The Recalcitrant Cancer Act of 2012 led the National Institutes of Health to dedicate a pool of money for cancers with very low survival rates, such as SCLC and pancreatic cancer. Funding driven by the act led to the founding of the NCI SCLC Consortium, which has to date led to more than $20 million in funding for SCLC research and more than 600 collaborative publications between US and international researchers.
In terms of concrete progress, funding through the act has led to the development of cell line and mouse models to study SCLC; furthered our understanding of the biomarkers in SCLC at the DNA, RNA, and protein level, including our understanding of the four subtypes of SCLC; and led to engagement with industry and biotech for new drug development. The act is the perfect testimony to how political advocacy, researchers all over the world, and pharma partners have joined hands to move the needle on subduing this aggressive disease.
Dr. Rudin noted that we have come a long way in the treatment of SCLC—both for LS-SCLC and ES-SCLC. However, we still have a long way to go, and this intersection of basic and clinical research will continue to drive change.
It was incredibly humbling to see so many of our past and current translational research awardees who are making a difference in the SCLC landscape. LUNGevity is honored to support so many research projects in this space. I cannot wait to see the SCLC research community at the 2024 meeting. If this meeting is proof of what progress looks like, I do not think I will be disappointed.