Metabolic Interventions Improve Cancer Treatment Delivery
A conversation between Jun Gong, MD, Cedars-Sinai, and Life Science Connect’s Michelle Raley
Could effective drug delivery depend not only on getting more therapy into a tumor but also on changing the tumor’s biological response to treatment? That question is central to the Phase 1 GlutaPanc trial, which evaluated high-dose oral L-glutamine as a therapeutic sensitizer alongside gemcitabine and nab-paclitaxel in advanced pancreatic ductal adenocarcinoma (PDAC).
The approach challenges the conventional emphasis on glutamine deprivation by investigating whether supplementation can exploit KRAS-regulated metabolic vulnerabilities. In this Q&A, Life Science Connect’s Michelle Raley connected with Jun Gong, MD, of Cedars-Sinai, to discuss the implications for drug delivery and the broader effort to translate metabolic insights into meaningful benefits for patients.
Many drug delivery discussions focus on carriers, formulations, or targeting technologies. Your research highlights a metabolic intervention alongside chemotherapy. How do you see tumor metabolism emerging as a complementary drug delivery strategy, one that potentially makes cancer cells more vulnerable to existing therapies rather than simply improving how drugs reach the tumor?
Targeting tumor metabolism represents an innovative therapeutic strategy in oncology. Unlike technologies or platforms that improve delivery of drugs to the tumor, the approach highlighted in the Phase 1 GlutaPanc trial would target metabolism inherent to the tumor that is vital for cancer cell growth and proliferation.
In the instance of PDAC, targeting KRAS-regulated glutamine metabolism uniquely exploits PDAC reliance on glutamine to exploit its metabolic vulnerabilities. As tumor metabolism is a hallmark of cancer, exploiting tumor metabolism represents an emerging drug delivery strategy that would usurp the need for delivery of focused concentrations of drug directly to the tumor; rather, it would target each cancer’s unique metabolic vulnerabilities.
This approach is unique in that it would not theoretically rely on specific drug delivery technologies such as carriers, formulations, or targeting technologies, but instead any compound that can be absorbed systemically to be reliably utilized by tumor-intrinsic and host mechanisms to alter metabolism for clinical benefit.
Pancreatic cancer has long been considered one of the most difficult solid tumors for effective drug penetration because of its dense stromal architecture and complex microenvironment. Looking broadly at the field, what advances do you believe hold the greatest promise for overcoming these biological delivery barriers over the next decade?
Pancreatic cancer is characterized by progressive therapeutic resistance and cachexia, both major contributors of its poor prognosis globally. Thus, improvements must be made in these two arenas to achieve meaningful outcomes for patients with PDAC. As many patients may not reach second- or third-line systemic treatments with advanced disease, we positioned L-glutamine in the first-line setting to optimize systemic therapies early in advanced disease, where many patients may benefit.
Targeting a canonical oncogenic driver has been a classic approach for cancer therapy. In PDAC, KRAS is highly prevalent across cases but has been historically undruggable. With the advent of pan-RAS and allele-specific KRAS inhibitors, these novel agents have changed the treatment landscape in PDAC.
On this note, RAS inhibitors are moving earlier and earlier in the treatment paradigm as well, with first-line trials underway. For example, the recently FDA-approved pan-RAS inhibitor, daraxonrasib, is being studied in a Phase 3 randomized controlled trial in combination with gemcitabine/nab-paclitaxel in the first-line treatment of metastatic PDAC. Thus, there is an emerging concept to use your best agents first for best chance of improved outcomes in PDAC.
The exquisite safety of L-glutamine and the fact that we studied the same gemcitabine/nab-paclitaxel chemotherapy backbone would render it attractive to combine with RAS inhibitors in earlier treatment settings for advanced PDAC. Rational combinations that are novel and safe would therefore represent an important strategy to optimize therapeutic outcomes in the first-line treatment of metastatic PDAC.
Lastly, we demonstrated anti-cachexia properties of L-glutamine that would render it important to study its ability to mitigate PDAC cachexia, while in combination with systemic therapies. For example, the majority of patients entering the GlutaPanc trial were cachectic by definition, but 50% of patients enrolled experienced weight gain or weight stability over the duration of study treatment. Glutamine has historically been shown to reverse cachexia in preclinical cachexia cancer models. The weight-stabilizing effects we observed are encouraging and supportive of the potential anti-cachexia properties of L-glutamine. This would add to its potential to overcome therapeutic barriers that have proved PDAC difficult to treat over the past decade given that cachexia is a poor prognostic indicator, affects quality of life, affects systemic treatment tolerance, and is a major cause of morbidity/mortality in patients with PDAC.
If metabolic support strategies such as glutamine supplementation ultimately prove beneficial, what might that teach us about the relationship between host metabolism, tumor biology, and therapeutic delivery more broadly? Are there lessons here that could extend to other hard-to-treat cancers?
It would be important to understand that tumor metabolism is often regulated by tumor biology, and vice versa. Not all tumors may benefit from metabolic support strategies such as glutamine supplementation, if they, for example, are not heavily KRAS-driven, as PDAC has shown to be heavily dependent on KRAS-regulated glutamine metabolism. Glutamine supplementation may prove successful, however, in other KRAS-driven tumor types.
Additionally, once you identify a metabolic strategy, drug delivery may still pose an important challenge. Glutamine is not water soluble, which limits its intravenous administration. However, based on our Phase 1 GlutaPanc trial, it may actually prove important for oral administration of L-glutamine so it can be metabolized by gut bacteria, where it may have additional benefits on promoting gut health, preserving gut barrier integrity, and improving malabsorption.
Historically, oncology has often discovered effective combinations through trial and error. How is our growing understanding of cancer metabolism changing that paradigm, and what biomarkers or patient selection approaches will be most important for making future drug delivery and combination strategies more precise?
The GlutaPanc trial is a good example of trial and error and the importance of sometimes challenging the convention in cancer metabolism. It is important to realize that glutamine deprivation, rather than supplementation, has been the historical approach to targeting glutamine metabolism in PDAC. The glutamine dependency in PDAC is uniquely driven by the KRAS oncogene, which is highly prevalent in PDAC cases. However, prior studies have proved that glutamine deprivation’s antitumor effects in PDAC preclinical models are short-lived, with translation to the clinical context challenging.
The Phase 1 GlutaPanc trial thus represents the first formal translation of glutamine supplementation using an FDA-approved, clinical-grade oral L-glutamine formulation as a therapeutic sensitizer to standard chemotherapy in advanced PDAC patients. It challenges the dogma that glutamine deprivation is the conventional therapeutic approach and supports the idea that pairing high-dose glutamine with gemcitabine/nab-paclitaxel chemotherapy is safe and feasible.
Many promising mechanistic insights never translate into meaningful patient benefit. From your perspective as a physician-scientist, what are the key factors that determine whether a novel drug delivery or tumor-sensitizing concept successfully crosses the gap from laboratory hypothesis to clinical practice?
I do have a few observations about successful bench to bedside translations in oncology. Firstly, there should be robust preclinical data to support the rationale and mechanisms of action for a systemic agent. If there is a biomarker involved, this biomarker and its relevant pathway should be studied in the relevant preclinical models showing on-target effect or predictive potential with reasonable expression of the biomarker in the tumor type of question. When translating to first human subjects, dose-finding Phase 1 trials including pharmacokinetics and pharmacodynamics are important for establishing the safety of the drug and effectiveness of the drug delivery system.
The biomarker or molecular target should again be validated in these human subjects to support the feasible translation from preclinical studies. Then, defining success by the appropriate metric in a larger study would be important. In cachexia studies, for example, this could include the classical OS, but measures of anti-cachexia efficacy such as weight loss, weight stability, and body composition would be just as important. Having an already available clinical-grade drug available for clinical translation would rapidly streamline the development pathway as well.
When we look ahead 10 years, what do you think the industry may be getting wrong about drug delivery today? What emerging scientific principles, whether related to metabolism, the tumor microenvironment, patient biology, or treatment sequencing, could fundamentally reshape how we think about delivering effective cancer therapies?
It often isn’t how much drug or the number of drugs you pile on; more drugs do not necessarily translate to better therapeutic outcomes, especially if toxicity becomes a factor. Advanced cancers will still heavily rely on improvements in systemic control, but better systemic control could come with more precise targeting of molecular targets relevant to that cancer type. And it may not be a single oncogene that does this but a constellation of molecular targets that may underscore the concept that the best systemic control may result from agents that cover multiple proteins and pathways. Systemic control could also be afforded by improved drug delivery, of course, but also with better safety. That is, if there is a safer alternative or a method that lessens toxicity, this would be an underappreciated strategy to optimize therapeutic outcomes while maintaining quality of life.
Beyond advanced-stage cancers, more focus should be placed on prevention, as that can be a tremendous avenue to improve cancer outcomes. Lastly, optimizing strategies to achieve cure in non-metastatic settings with surgery and other local therapies would also be an important setting to improve outcomes.
About The Expert:
Jun Gong, MD, is a medical oncologist, Associate Professor of Medicine, and Medical Director of Colorectal Cancer at Cedars-Sinai. He specializes in gastrointestinal, hepatobiliary, and genitourinary cancers, providing multidisciplinary care in collaboration with specialists across surgery, gastroenterology, radiation oncology, radiology, and urology. Gong’s research focuses on developing new approaches to cancer treatment, including immunotherapy, targeted therapies, biologics, and other systemic therapies, as well as biomarkers designed to improve patient outcomes. He earned his medical degree from New York Medical College and completed his hematology/oncology fellowship at City of Hope, where he also served as Chief Fellow.