Meeting the Editorial Board Member of TLCR: Dr. Jaime L. Schneider

Posted On 2024-05-17 10:09:36


Jaime L. Schneider1, Jin Ye Yeo2

1Massachusetts General Hospital Cancer Center and Department of Medicine, Boston, MA, USA; Harvard Medical School, Boston, MA, USA; 2TLCR Editorial Office, AME Publishing Company

Correspondence to: Jin Ye Yeo. TLCR Editorial Office, AME Publishing Company. Email: editors@TLCR.org

This interview can be cited as: Schneider JL, Yeo JY. Meeting the Editorial Board Member of TLCR: Dr. Jaime L. Schneider. Transl Lung Cancer Res. 2024. https://tlcr.amegroups.org/post/view/meeting-the-editorial-board-member-of-tlcr-dr-jaime-l-schneider.


Expert Introduction

Dr. Jaime L. Schneider (Figure 1) is a medical oncologist at the Massachusetts General Hospital (MGH) specializing the care of patients with thoracic malignancies. Dr. Schneider received her B.A. from Northwestern University and her M.D./Ph.D. degrees from the Albert Einstein College of Medicine. After completing her residency in internal medicine at the Massachusetts General Hospital and fellowship in medical oncology in the Dana-Farber/Harvard Cancer Care program, she joined the faculty as an Attending Physician in the Center for Thoracic Cancers at MGH Cancer Center and is an instructor at Harvard Medical School. Dr. Schneider has an active practice caring for patients in the MGH Thoracic Oncology Program.

As a basic/translational investigator, Dr. Schneider’s research focuses on non-small cell lung cancer, with a specific interest in cancers that harbor oncogenic driver alterations. Using clinical specimens and patient-derived models, she is using integrative metabolomics approaches to identify resistance mechanisms in oncogene-driven lung cancer. She is investigating whether specific oncogenotypes in lung cancer confer metabolic vulnerabilities and how metabolic reprogramming underlies resistance to targeted therapies. As a physician-scientist, Dr. Schneider is passionate about treating patients with lung cancer and is committed to developing novel therapeutic approaches using innovative scientific tools.

Figure 1 Dr. Jaime L. Schneider


Interview

TLCR: What drove you into the field of lung cancer, specifically oncogene-driven lung cancer?

Dr. Schneider: Lung cancer remains the number one cause of cancer-related death, a sobering statistic that holds true in the U.S. and worldwide. In the US, there are over 230,000 new cases of lung cancer diagnosed every year and over 120,000 lung cancer-related deaths according to the most recent data (1). Approximately 44% of all lung cancer cases are diagnosed when patients already have a distant spread of the disease and five-year relative survival for lung cancer in the U.S. is only 25% (1). We clearly have room for improvement.

There is some good news, though. As rates of smoking in both men and women continue to decline, we have observed an encouraging decrease in lung cancer incidence over the last few decades. Population-level mortality from non-small cell lung cancer (NSCLC) has fallen and survival after diagnosis has improved substantially (2). This is attributable not just to a reduction in incidence from a decline in smoking but is also due to the incorporation of new types of treatments into our clinical practice. Furthermore, the implementation of low-dose computed tomography (CT) scans to screen for early-stage lung cancer has helped us catch disease at earlier stages prior to metastatic spread (3). Continuing public health measures to cut smoking rates and expand lung cancer screening will be critical to help us cure more people.

With that being said, there are still many challenges we face. Despite clear national guideline recommendations, screening rates for lung cancer are actually horrifyingly low across the country. My state of residence, Massachusetts, is among the top in terms of the percentage of high-risk populations receiving screening, but that is only around 10-15% (American Lung Association). Without better uptake of screening, we will unfortunately continue to diagnose lung cancers at later stages when a cure is much less likely. While smoking-related lung cancers are on the decline, non-smoking-related lung cancers are on the rise. Currently, we do not screen for early-stage lung cancers in people who have never smoked, a topic that is being actively investigated.

All of that is to say that we have a lot left to learn across the board in terms of screening, epidemiology, risk factors, disease biology, and therapeutics. As a physician scientist, I became deeply interested in lung cancers that harbor actionable oncogenic driver alterations, which are enriched in younger patients without a significant history of smoking. As I was learning about these distinct molecular subtypes of lung cancer during my fellowship training, I could not help but wonder what is different about the molecular dependencies of these patients. Why is the incidence so high in younger patients? What is different about early-onset lung cancers in patients without clear risk factors? How do these oncogenic drivers coopt downstream pathways to drive proliferation? If these subtypes of lung cancer are so ultra-dependent on the oncogenic driver alteration, why are targeted therapies not curative?  

TLCR: Could you provide an overview of the current landscape of the field’s understanding of oncogene-driven lung cancer?

Dr. Schneider: Great question. First, let’s take a step back and ask ourselves how we define oncogene-driven cancers. After all, the vast majority of tumors harbor at least one somatic alteration (4) and those that do not may be false negatives given the use of panel-based sequencing as opposed to whole exome or whole genome sequencing methodologies. Among those patients that harbor activating somatic alterations in driver genes, how do we differentiate between true driver versus passenger alterations? How do we know which genomic aberrations actually matter? To me, the strongest data to support the categorization of a genomic alteration as a true oncogenic driver in lung cancer is the induction of tumor response with its pharmacologic inhibition. This, however, depends on many factors including drug potency, selectivity, biodistribution, confounding mutations, and intrinsic resistance.

Although we have a large arsenal of targeted therapies directed towards oncogenic drivers in lung cancer, I find it helpful to think about the first molecularly targeted agents which were developed for other cancer types which helped set the stage for our understanding of oncogene-driven disease in NSCLC. The prototypical example of the first tyrosine kinase inhibitor (TKI) was the ABL inhibitor, imatinib, for patients with chronic myeloid leukemia (CML) which targeted the BCR-ABL fusion event and received U.S. Food and Drug Administration (FDA) approval in 2001. One can go back even further to include Tamoxifen as one of the first targeted therapies by virtue of its selective inhibition of the estrogen receptor, initially FDA-approved for advanced breast cancer in 1977.

These agents set the precedence for our understanding of how to treat biomarker-positive disease, as imatinib demonstrated efficacy only in those patients whose tumors harbored an ABL fusion and tamoxifen in those with hormone receptor-positive breast cancer. This framework laid the groundwork for the molecular characterization of tumors, a concept that was critical to identifying the subpopulation of lung cancer patients who benefitted from EGFR inhibitors in 2004: those who harbored mutations in EGFR (5).

Today, it is a Category 1 National Comprehensive Cancer Network (NCCN) recommendation that physicians perform broad molecular profiling at initial diagnosis in patients with advanced non-small cell lung cancer. This goes beyond testing for just EGFR mutations and includes an array of actionable oncogenic driver alterations including ALK, ROS1, RET, NTRK1/2/3, METex14, KRAS, BRAF, ERBB2 (HER2). Multiplexed NGS testing is also useful to identify genomic alterations beyond those listed above, as it may find other drivers that have targeted agents being evaluated in clinical trials. At this point, numerous studies have demonstrated improvement in the survival of advanced NSCLC patients who received matched targeted therapy for oncogenic driver alteration (6,7). Yet, there are unacceptable gaps in biomarker testing, evidenced by low uptake of NGS despite national guidelines (8). This is a complicated area with an array of challenges, but the bottom line is we must do better for our patients.

Beyond therapeutic targeting of these drivers, I think there are other important considerations when studying the disease biology of oncogene-driven lung cancers. For instance, what transduces the signals from the mutant oncogenic protein to exert a tumorigenic effect? While most investigation has traditionally focused on the interrogation of downstream signaling pathways, I think we still have a lot to learn about other mediators that link the oncogenic alteration with carcinogenic potential. To that end, one focus of my research is understanding whether specific oncogenotypes confer metabolic dependencies. One can imagine that if we find key mediators downstream of these oncogenic alterations that are critical for transducing oncogenic signals, we can develop therapeutics that can potentiate TKIs, thwart resistance, and perhaps induce cure.

Beyond cancers that originate in the lung, there continues to be an expansion of targeted therapies agents approved for oncogene-driven cancers. In fact, there are now several approvals for molecularly targeted agents in a tissue-agnostic fashion. Tissue-agnostic therapies are used to treat cancers based on their genetic and molecular features without regard to the cancer type or where the cancer started in the body (National Institutes of Health). For instance, those patients with NTRK fusion-positive cancers, irrespective of tissue of origin, can be treated based on their cancer genomic features (9). This extends to small molecule inhibitors for RET fusion-positive or BRAF V600E-mutant cancers, immunotherapy for MSI-high cancers, and most recently, an antibody-drug conjugate for HER2-positive solid tumors (10). With more emerging targets both in lung cancer and in tissue-agnostic contexts, I think it will be critical to tease out which disease modifiers confer sensitivity across tissue types and to delineate inherent molecular mechanisms of resistance.

TLCR: What inspired you to start investigating tumor metabolism changes in oncogene-driven lung cancer?

Dr. Schneider: During my graduate school training, I elected to take a course called “Biochemistry of Metabolic Regulation” which explored metabolic mechanisms of human disease. I was struck by how many pathophysiologic conditions, cancer included, are driven by dysregulated metabolic states. For my PhD training, I joined the laboratory of Dr. Ana Maria Cuervo, M.D., Ph.D., a highly accomplished researcher in the field of autophagy and a truly exceptional mentor to trainees. At that time, I was interested in understanding the crosstalk between proteostasis pathways, specifically dissecting interconnectedness between proteasomal and lysosomal protein degradation systems. Even though I started off my graduate training with a focus on protein homeostasis, my projects took a turn towards metabolism when I developed the first mouse model of selective autophagy deficiency which turned out to have a metabolic phenotype (11). I spent the better part of my thesis thinking about how the regulation of protein degradation directly modulates metabolite availability and metabolic flux (12-14). This experience was instrumental in reshaping the way I viewed the central dogma of molecular biology in that metabolites are really the functional output of gene expression and protein regulation.

By the time I started my post-graduate training at the Massachusetts General Hospital (MGH) as a physician scientist, I had a clear idea of wanting to pursue a career in academic medicine in the field of oncology. The concept of treating cancer patients while actively exploring better ways to understand their disease in the laboratory has always been a driving force throughout my training. During my clinical fellowship in the Dana Farber Cancer Institute/Harvard Cancer Center program, I became passionate about treating patients with lung cancers. I was blown away by the rapid pace of regulatory approvals of targeted therapy agents and the burgeoning field of tissue-agnostic therapies across cancer types.

During my post-doctoral work in the laboratory of Dr. Marcia Haigis, Ph.D., at Harvard Medical School, I wanted to draw from my expertise in metabolism and focus my research efforts on identifying novel metabolic mechanisms of resistance to targeted therapies. Although altered metabolic states in cancer have been appreciated for over a century (15), the field has yet to fully delineate how metabolic dysregulation is conferred by distinct oncogenic drivers. Data suggests that lung cancer cells reprogram pathways of nutrient acquisition and metabolism to meet the bioenergetic demands of malignant tumors (16). As such, there are over a dozen clinical trials evaluating small-molecule metabolic inhibitors in various cancer subtypes (17). Thus, I felt that targeting cancer metabolism in the era of precision oncology offers a fresh approach to interfere with critical pathways used by cancer cells in a more selective manner.

Therefore, I have honed in on understanding dysregulated metabolic states in lung cancer by asking two central questions: 1) can we identify unique metabolic vulnerabilities in molecular subsets of lung cancer, and 2) how does metabolic reprogramming drive resistance to targeted therapy? As a basic/translational investigator and a clinician seeing patients with lung cancer, my professional mission is defined by pursuing meaningful translational research that can have consequential impacts on the lives of patients with lung cancer. Breakthroughs in this arena have the potential to identify metabolic biomarkers of resistance and can set the framework for a new paradigm in which modulation of metabolism can be a clinically actionable lung cancer treatment. 

TLCR: In your most recent research, your team identified multiple layers of mesenchymal-epithelial transition (MET) axis activation involved in driving drug resistance in ROS1-rearranged lung cancer (18). How do you foresee this finding to contribute to ongoing efforts to circumvent the evolution of drug resistance in ROS1-rearranged lung cancer?

Dr. Schneider: Acquired resistance to targeted therapy is universal, persistent challenge across all oncogene-driven lung cancers in which we use targeted therapies. This is an incredibly important area to study because this shared theme of acquired resistant limits the duration of efficacy of the TKI).

We broadly categorize TKI resistance as either on-target or off-target. On-target (or oncogene-dependent) resistance typically refers to acquired mutations in the initial oncogenic driver that render TKIs ineffective. Next-generation inhibitors that are increasingly potent, selective, CNS penetrant, and have broader coverage against resistance alterations have helped, to some extent, address on-target resistance. Off-target (or oncogene-independent) resistance refers to other pathways that are reprogrammed to support tumor proliferation independent of the initial oncogenic driver (19). This may happen through upregulation of bypass signaling pathways, lineage transformation, or still unappreciated non-genomic mechanisms of resistance.

In our recent publication, we reported a case of a patient with ROS1 fusion-positive NSCLC who developed acquired MET amplification as a resistance driver after sequential treatment with ROS1 TKIs (18). The patient had a dramatic, albeit short-lived, response to combination therapy with dual inhibition of ROS1 and MET. At the time of relapse, sequencing revealed an on-target resistance alteration in MET and concomitant loss of the MET amplification. This case is instructive for several reasons, as it 1) establishes MET-driven disease as a bona fide mechanism of resistance in ROS1+ NSCLC, 2) highlights the advantages and challenges of integrated next-generation sequencing (NGS) using both serial plasma and tumor specimens, 3) underscores the complexity of longitudinal tumor evolution with sequential targeted therapies, 4) emphasizes the importance of considering approaches that prevent resistance rather playing “whack-a-mole” once resistant clones arise.

Ultimately, new therapeutic strategies such as up-front use of next-generation agents or TKI combinations may be beneficial to suppress the emergence of on-target resistance mechanisms and mitigate opportunities for cells to evolve off-target escape pathways. This case also highlights the many challenges of therapeutic targeting of off-target resistance. For instance, as our arsenal of targeted therapy in lung cancer continues to expand, circumstances may arise in which multiple heterogeneous resistance mechanisms are detected with either FDA-approved or investigational drugs available, making it challenging to decide which, if any, warrants therapeutic targeting.

TLCR: What are the next steps in your research? Could you share some of the current projects that you are working on now, or what you hope to achieve in the next few years?

Dr. Schneider: I conduct basic/translational research focusing on patients whose tumors harbor oncogenic driver alterations, with a particular interest in oncogenic fusion tyrosine kinases and the intersection of signaling and metabolism. We employ various techniques to interrogate reprogrammed tumor metabolism in oncogene-driven lung cancer including use of steady-state and tracing metabolomics in patient-derived cell culture models pre- and post-TKI resistance, targeted/untargeted metabolomics in mouse models of lung cancer and in patient specimens, integration of metabolite signatures by combining imaging mass spectroscopy with histology to reveal spatial distribution of metabolites, and phosphoproteomics to identify regulatory post-translational modifications of metabolic enzymes.

One major focus of my work is identifying oncogenotype-specific metabolic dependencies and uncovering how metabolic reprogramming drives resistance to targeted therapies. Although dysregulated tumor metabolic states have been appreciated for over a century15, little is known about metabolic vulnerabilities in subsets of oncogene-driven lung cancer. To this end, we recently executed an integrative phosphoproteomics and metabolomics analysis in anaplastic lymphoma kinase (ALK)-rearranged (“ALK+”) patient-derived cell lines pre- and post-resistance, and we identified several metabolic enzymes that are novel targets of oncogenic signalling. We also found that a subset of patients who develop resistance to TKIs exhibit different regulation of proteins that control critical nodes of metabolism. Uncovering differential regulation of metabolic enzymes in TKI-refractory disease offers a new paradigm of resistance to targeted therapy, and thus creates an opportunity for developing novel therapeutic strategies. As such, we are working on developing novel small molecule inhibitors to interfere with critical pathways that lung tumors rely on to sustain growth. Future directions of our work also include expanding our understanding of how cancers rewire their anabolic and catabolic networks once they develop resistance to targeted therapies, which helps to address a major gap in our understanding of non-genomic resistance mechanisms.

TLCR: What are some of the most pertinent challenges you faced during your research studying oncogene-driven lung cancer? Moving forward, what do you think should be the research direction to overcome these challenges?

Dr. Schneider: Targeted therapies have clearly revolutionized the diagnostic and treatment approach to advanced lung cancer (20). Excitingly, these agents are now moving into earlier stages of lung cancer treatment with the goal of curing more patients in the adjuvant setting (21,22).

As a treating physician, I have been moved to observe how oral TKIs have supplanted intravenous chemotherapy as first-line treatment options and to witness first-hand how they improve quality of life, symptoms, and survival for my patients. However, as a scientist, I am intrigued about why targeted therapies aren’t curative. If lung cancers arise de novo to be ultra-dependent on a distinct oncogenic driver alteration and we have highly potent and selective inhibitors with excellent biodistribution, why can’t we induce cure, even in the metastatic setting?

We often blame this on therapeutic resistance – whether intrinsic or acquired. This problem of acquired resistance to targeted therapy is pervasive across oncogenic drivers in lung cancer and is relevant to a myriad of other cancer types we treated with targeted agents. The continued development of next-generation targeted therapies to overcome TKI-refractory disease is critical. Beyond expanding our drug development pipeline, fundamental questions also remain regarding how to block the emergence of polyclonal resistance, eradicate persister cells, and ultimately induce cure in metastatic disease. A singular TKI or even polytherapy may not be able to achieve this goal, so incorporation of orthogonal treatment modalities may prove integral.

I think of three main research directions that would help to address these challenges. First, we need a better understanding of persister cell biology, including what accounts for the survival of pre-existing drug-tolerant cells and treatment-induced drug tolerance. For this to happen, I would argue that better laboratory-based models are needed to study persister cell mechanisms of survival. Moreover, we need more on-treatment biopsies from patients to ensure we are capturing biology that is relevant in vivo. As an extension of this idea, we also need highly sensitive diagnostic methods to track tumor response and to detect microscopic residual or recurrent disease. Tremendous progress is being made in cell-free plasma analysis of different analytes (23), but more studies are needed to further clarify adaptive therapeutic escalation or de-escalation based on serial monitoring.

Secondly, we need better assessments of how the incorporation of orthogonal treatment modalities (chemotherapy, radiation, epigenetic- or immune-based strategies, metabolic manipulation) may help to eliminate residual disease and perhaps prevent relapse altogether. Intuitively, it makes sense to implement combinations early, i.e. prior to radiographic evidence of clinical relapse, but we need more prospective studies to disentangle the trade-offs of efficacy and toxicity.

Thirdly, while tissue genotyping at the time of diagnosis and at disease progression has informed on the landscape of acquired resistance alterations (both on- and off-target), we are still not systematically capturing non-genomic mechanisms of resistance. By executing panel-based sequencing, we are missing a large percentage of patients who lack any genomic alterations but may indeed have epigenetic, transcriptional, proteomic, or metabolic drivers of therapeutic resistance. As a field, we need better ways to analyze non-genomic mechanisms of resistance, including high-throughput profiling of clinical specimens and more emphasis on their functional characterization in the laboratory.

TLCR: How has your experience been serving as an editorial board member of TLCR?

Dr. Schneider: Serving as an editorial board member of TLCR has been a privilege. The role enables me to keep up to date on the latest studies in translational lung cancer research. One unexpected advantage has been the ability to keep abreast of new ways to model lung cancer in the laboratory. This is something we struggle with as basic/translational investigators: how do we recapitulate the complex array of cellular, molecular, immune, and metabolic features of lung tumors in a patient and faithfully model them in the laboratory? Being involved as an editor for TLCR has opened my eyes to various approaches used by investigators to model lung cancer through patient-derived cell culture models, syngeneic and transgenic rodent models, and primary as well as metastatic patient-tumor specimens. In particular, cautious consideration of model choice is critical when investigating mechanisms of therapeutic resistance in the laboratory, as there are significant challenges given their heterogeneity and the facile adaptations of treatment-refractory tumor cells to their local environment. Serving as an editor has provided me the opportunity to learn from other investigators on a larger scale and on the flip side, ensure the quality of translational studies is held to the highest possible bar. We are all working towards a simple, common goal: bettering the lives of our patients.

TLCR: As an Editorial Board Member, what are your expectations for TLCR? Would you like to provide any suggestions for the development of TLCR?

Dr. Schneider: TLCR is a unique journal as its core mission is defined by highlighting studies with translational impact. As a physician scientist, I am constantly thinking about ways to expand my translational program. How can I execute the “bench to bedside” and “bedside to bench” paradigm to the absolute best of my ability? I anticipate TLCR will continue to grow in its role in helping translational investigators achieve those goals through providing key resources to the community. Especially with the growing list of new treatments for lung cancer patients (next-generation targeted therapies, novel immunotherapies, antibody-drug conjugates), TLCR will continue to cement its importance and serve as a hub for investigators to share novel findings and cultivate ideas for transforming the field.


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