Health Equity and Inclusiveness Research Fellow Award

Role of the RNA Modifier METTL3 in Lung Cancer

2023

Maria Trovero, PhD

Boston Children's Hospital

Boston

In this project, Dr. Trovero will study the role of METTL3, an RNA modifying protein that is thought to promote tumor initiation and progression. She will evaluate the function of METTL3 by increasing or decreasing its activity in vivo. Results from this study will help establish METTL3 as a possible therapeutic target for lung cancer, and pave the way for understanding the relationship between RNA modifiers and cancer biology.

Research Summary

Lung adenocarcinoma (LUAD) is the leading cause of death from cancer worldwide. The survival rate for lung cancer is only about 18%, highlighting the need for more effective treatments. DNA is encoded in our genomes to make RNA, which encodes proteins. However, RNA can have important functions in our cells independent of making proteins, such as exquisite regulation of gene expression. RNA can also undergo chemical modifications. However, the role of RNA modifications in cancer is still poorly understood. METTL3, a protein that modifies RNA, has emerged as a possible oncogene, a gene that promotes tumor growth. Our collaborator Dr. Richard Gregory discovered that METTL3 activity benefits the growth, survival, and invasion of human cancer cell lines (what we call “in vitro”). I aim to explore the role of METTL3 in LUAD initiation and progression in models that more closely resemble reality (“in vivo”). I will evaluate the function of METTL3 in a LUAD mouse model, by studying the effects of decreasing or increasing METTL3 activity on tumor development. I also want to test how METTL3 impacts early stages of lung cancer. Thus, I will manipulate METTL3 expression in a lung tumor organoid system (a simplified 3-dimensional version of an organ generated from stem cells, that recapitulates in vivo tumor growth). The results of this proposal will help to establish METTL3 as a possible future therapeutic target for lung cancer. This investigation could also pave the way for understanding the links between RNA modifiers and cancer biology.

Technical Abstract

Among mRNA modifications, N6- Methyladenosine (m6A) is the most abundant, catalyzed by a complex that includes methyltransferase-like 3 (METTL3). Although the function of m6A in cancer remains understudied, Gregory’s lab provided functional evidence of METTL3 as an oncogenic protein, promoting translation of oncogenes to promote lung cancer cell growth, survival, and invasion in human cancer cell lines. Lung adenocarcinoma (LUAD) is the most common form of lung cancer, with a survival rate of about 18%, highlighting the need for more effective treatments and understanding LUAD biology.

Our hypothesis: METTL3 is a novel oncogenic factor in lung cancer and plays a key role in tumor initiation and progression. I will test the role of METTL3 in a LUAD mouse model, and in tumor organoid culture system.

Aim 1: Determine the effects of METTL3 manipulation on tumor progression in a LUAD mouse model. Lentivirus will be used to knockdown or overexpress METTL3 simultaneously with activation of oncogenic Kras in the LUAD mouse model for comparison of tumor number, size and histopathological features.

Aim 2: Test the effects of METTL3 on early-stage lung cancer by manipulating METTL3 expression in a tumor organoid model of cancer initiation. Alveolar epithelial (AT2) cells from Kras mice will be infected with Cre and shMETTL3 or METTL3 cDNA to initiate early-stage lung cancer in organoid cultures, to assess organoid size, proliferation and differentiation features.

This proposal could establish METTL3 as a therapeutic target for lung cancer and pave the way for understanding links between epitranscriptome and cancer biology.

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TROP2 Directed CAR T in NSCLC as a Strategy for Eradicating Persister MRD

2023

Health Equity and Inclusiveness Research Fellow Award

Elliott Brea, MD, PhD

Dana-Farber Cancer Institute

Boston

This project proposes to develop novel therapeutic approaches to treat advanced EGFR-mutant NSCLC. CAR-T cell therapy is a type of immunotherapy treatment that uses genetically altered T cells to find and destroy cancer cells more effectively. TROP2 is a protein that is over expressed on the surface of NSCLC and is a target of the antibody-drug conjugate (ADC), sacitizumab-govitecan, which is FDA-approved to treat other solid tumors. Dr. Brea hypothesizes that TROP2-directed CAR-T targeting of EGFR-mutant NSCLC will be superior to standard Osimertinib treatment.

Research Summary

While advances have been made in treating advanced or metastatic cases of Non-small cell lung cancer (NSCLC) with either targeted therapy or immunotherapy, most patients will progress after these first line therapies and require subsequent treatments which are limited in efficacy. EGFR mutant (EGFRm) lung adenocarcinoma is the most common type of NSCLC in patients without a history of tobacco use. They often respond to first line treatments called EGFR inhibitors (EGFRi) that target or block EGFR but unfortunately this is usually not curative in patients with advanced or metastatic EGFR mutant lung cancer. Chimeric antigen receptor T-cell therapy (CAR-T) works by engineering a patient’s immune fighting cells called T-cells to fight the cancer utilizing a receptor, which is matched to proteins expressed on the cell surface of cancer cells. When the receptor recognizes the cancer- associated proteins, T cells bring their powerful anti-cancer attack directly to the malignant cells. CAR-T has shown significant promise in blood cancers with durable responses observed. TROP2 is a protein present in NSCLC and is the target of FDA approved antibody-drug conjugate (ADC) sacitizumab-govitecan for breast and bladder cancer and is in clinical trials for lung cancer. Our goal is to demonstrate that TROP2 directed CAR-T cell therapy is effective in NSCLC, and can eradicate disease in a more durable fashion when compared to standard therapy with EGFRi. We plan to use the results of this work to translate this to clinical trials evaluating this promising strategy for treating lung cancer.

Technical Abstract

While immunotherapies in cancer have allowed for major advances in the field, most patients with advanced or metastatic solid tumors do not achieve durable responses. While CAR-T cell therapy and bispecific antibody therapies which utilize T-cells as their effector have shown promise and durable responses in hematologic malignancies such as DLBCL and multiple myeloma, the promise of similar responses in solid tumors remains an unmet goal. TROP2, a cell surface protein normally expressed during fetal development and at low levels in some normal adult tissue, is over expressed on a variety of solid tumors including NSCLC, and has emerged as an ideal target. TROP2 is the target of the recently FDA approved ADC sacitizumab-govitecan for breast cancer as well as for patients with locally advanced or metastatic urothelial cancer and is currently being tested in phase II/III trials in NSCLC. However, response in patients and in animal models are not durable, even when targeting minimal residual disease (MRD; defined as the residual disease after effective genotype directed systemic treatment). We propose utilizing TROP2 directed CAR-T to target EGFRm NSCLC at MRD, which we hypothesize when compared to TROP2 directed ADC will demonstrate a more durable response. Our preliminary data support the high activity of TROP2 directed CAR-T against EGFRm NSCLC including in the MRD state after osimertinib treatment. We expect these findings to translate to approaches utilizing CAR-T cellular therapy to target the MRD state after targeted therapy.

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Synergistic expression of combined RT and dual-immune checkpoint blockade

2022

Health Equity and Inclusiveness Research Fellow Award

Rebecca Shulman, MD

The Research Institute of Fox Chase Cancer Center

Philadelphia

Recent studies have shown that high and low dose radiation used in combination with immunotherapy have a synergistic effect in modulating the growth of satellite tumors, which are tumor cells located near the primary tumor. In this study, Dr. Shulman proposes using an animal model of metastatic lung cancer to test the hypothesis that radiation given in repeated very low dose pulses in combination with immunotherapy can further enhance immunotherapeutic benefit in metastatic lung cancer.

Research Summary

Radiation therapy has become a staple of cancer treatment because it provides a method for producing lethal damage in cancer cells while sparing nearby healthy tissues. Only more recently has it been shown that radiation may also control the growth of satellite tumors–tumors far from the radiation target. This capacity of radiation to affect tumors indirectly is called the abscopal effect and appears to occur because radiation of a small target area stimulates an immune system response throughout the entire body. The demonstration that radiation therapy can augment the body’s natural immune defenses in this way, producing regression of non-irradiated tumors, has led to a radical rethinking of the therapeutic uses of radiation. Thus, contemporary treatment strategies in radiation oncology are based not only on the capacity of radiation to kill cells directly but rely also on remote immune-mediated effects to destroy cancers that have spread. One of the most promising of such strategies involves a combination of radiation therapy and drugs that stimulate the immune system (immunotherapy). In our laboratory, we have tested such a regimen in a mouse model of disseminated lung cancer and have shown that high-dose radiation therapy delivered to select tumors in combination with two immunotherapy agents can significantly inhibit the growth of satellite tumors. We would now like to extend our results with immunotherapy and high-dose radiation by developing a protocol that further exploits the ability of radiation to work in synergy with our natural immune responses. Several research groups have reported favorable results combining immunotherapy both with high-dose radiation and with low-dose radiation delivered to other secondary tumors. Preliminary evidence, however, suggests that low-dose radiation may actually do more to enhance natural immune defenses if it is given in the form of repeated very low dose pulses. The present study will thus employ an animal model of disseminated lung cancer to test a new radiation protocol with possibly enhanced immune effects. The results will determine if the therapeutic efficacy of immunotherapy in combination with high-dose and low-dose radiation can be improved by the use of low-dose radiation given to satellite tumors in the form of repeated very low-dose pulses.

Technical Abstract

Our laboratory has demonstrated the potency of the abscopal effect in studies showing that high-dose radiation therapy delivered to primary tumors in combination with dual immune checkpoint blockade can significantly inhibit the growth of satellite tumors. The implication of such results is that radiation therapy has remote effects which are immune-mediated and that new radiation protocols can be devised to exploit our naturally occurring defenses against cancer. Previous studies have shown that immune-mediated tumoricidal effects can be augmented by combining high-dose radiation therapy delivered to a primary tumor site with low-dose radiotherapy (LDRT) targeting secondary tumors. Tumor response is further enhanced if systemic agents are employed to induce immune-checkpoint blockade (ICB). Such protocols employing conventional LDRT are known to reduce the number of regulatory T cells (Tregs) and to activate natural killer cells, thereby modulating the tumor microenvironment (TME). Our laboratory project seeks to test a modification of LDRT called pulsed low-dose-rate radiotherapy (PLDR). By providing radiation in repeated very low doses, the PLDR regimen may reduce the encasement of tumors with stromal elements, thus removing a barrier to infiltrating immune-reactive cells. We propose to use the immunocompetent lung cancer murine model which we developed for our earlier research combining HDRT with anti-PD1 and anti-CTLA-4 antibodies. HDRT will again be delivered to primary tumors in combination with dual ICB. Additionally, LDRT will be delivered to secondary tumors, both in conventional form and as PLDR. The results will thus test an innovative method for exploiting the emerging synergies of radiation and ICB. A demonstration of the superior therapeutic utility of PLDR in our animal model would be of immediate relevance to clinical trials seeking improved strategies for treating patients with metastatic lung cancer.

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Improving lung cancer screening adherence among underserved populations

2021

Health Equity and Inclusiveness Research Fellow Award

Eduardo Nunez, MD

Boston University School of Medicine

Boston

Technical Abstract

Lung cancer remains the leading cause of cancer death worldwide and clinical trials show that annual lung cancer screening with low-dose Computed Tomography can reduce lung cancer-related mortality by 20%. Marginalized populations are disproportionately affected by lung cancer and our prior work has shown that these disparities extend to lung cancer screening; in a national cohort of Veterans we found that Black Veterans, those with mental health disorders and lower income were less likely to adhere to lung cancer screening follow-up recommendations. Currently, little is known about how to optimize lung cancer screening in underserved populations and marginalized populations from diverse backgrounds.

This proposed project focuses on identifying barriers and facilitators to lung cancer screening at the patient, provider, facility and community-levels. We plan to use mixed methods to quantitatively explore factors associated with delayed or lack of adherence to lung cancer screening and then perform in-depth qualitative analysis to identify which factors are critical and modifiable. We will use an implementation strategy mapping tool to select evidence-based strategies best suited to address the identified barriers and develop a tailored implementation plan to improve adherence to lung cancer screening, both overall and among underserved populations, at Baystate Health System. This work is critical in achieving equity in lung cancer screening and improving overall lung cancer mortality among patients.

Key words

Early detection

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Health Equity and Inclusiveness Research Fellow Award

Role of the RNA Modifier METTL3 in Lung Cancer

TROP2 Directed CAR T in NSCLC as a Strategy for Eradicating Persister MRD

Synergistic expression of combined RT and dual-immune checkpoint blockade

Improving lung cancer screening adherence among underserved populations

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