The investigation began with a computational analysis of publicly available transcriptomic and clinical data from widely used prostate cancer cohorts. The researchers sought to identify genes whose expression patterns could reliably predict patient outcomes, a longstanding goal in the field of precision oncology. Using differential expression analysis to pinpoint genes that behaved differently between tumor and healthy tissue, the team then applied LASSO-Cox regression, a statistical technique that penalizes overly complex models to prevent overfitting and select only the most robust predictors. The result was a compact three-gene prognostic signature consisting of MECR, HVCN1, and NGFR. What makes this finding particularly striking is the model’s performance: the three-gene combination independently predicted patient survival and outperformed conventional clinicopathological variables such as stage, grade, and prostate-specific antigen levels, which clinicians have relied upon for decades. In clinical practice, this kind of molecular signature could eventually help stratify patients at diagnosis, identifying those who need intensified surveillance or more aggressive intervention even when traditional indicators appear reassuring.

Of the three genes in the signature, MECR emerged as the standout. Short for mitochondrial enoyl-CoA reductase, MECR encodes an enzyme embedded in the fatty acid synthesis machinery of mitochondria, and it was the only member of the trio whose elevated expression was associated with poor prognosis. This connection to lipid metabolism is scientifically significant because cancer cells are notorious for rewiring their metabolic programs to support rapid proliferation. Fatty acid synthesis, in particular, provides building blocks for membranes, energy storage, and signaling molecules that tumors need as they grow and spread. The observation that a mitochondrial enzyme in this pathway correlates with worse outcomes in prostate cancer suggested to the researchers that MECR might not merely be a biomarker but an active participant in the disease process.

To test this hypothesis, the team turned to functional experiments in prostate cancer cell lines. When they reduced MECR expression, the cancer cells lost several of their malignant advantages. Proliferation slowed, migration—the cellular behavior that underpins metastasis—was impaired, and the cells showed increased apoptosis-related nuclear morphological changes, meaning they displayed the characteristic structural hallmarks of programmed cell death. These results indicate that MECR helps prostate cancer cells resist apoptosis, the built-in suicide program that healthy organisms use to eliminate damaged or dangerous cells. Tumors that evade apoptosis are notoriously difficult to treat with chemotherapy and radiation, both of which work in part by triggering this death pathway. A gene that suppresses apoptosis therefore represents an attractive therapeutic target, because inhibiting it could potentially re-sensitize tumors to existing treatments.

The mechanistic story deepened when the researchers probed how MECR exerts its effects. Their experiments revealed that MECR regulates the activity of the PI3K/AKT pathway, one of the most frequently activated signaling cascades in human cancer. This pathway functions as a master switch for cell survival, growth, and metabolism; when constitutively active, it drives uncontrolled proliferation and protects cells from dying. By modulating PI3K/AKT signaling, MECR appears to sit upstream of processes that are central to tumor maintenance. Beyond this canonical cancer pathway, the team also found evidence that MECR influences immune-related cellular mechanisms, hinting that the gene’s impact extended beyond the tumor cell itself and into the surrounding microenvironment—the complex ecosystem of immune cells, fibroblasts, blood vessels, and signaling molecules that envelops every tumor.

That hint was put to a rigorous test using immunocompetent syngeneic tumor models, laboratory systems in which tumors are grown in mice with fully functioning immune systems. This experimental design is critical because many cancer studies rely on immunodeficient mice, which cannot reveal how a tumor interacts with the immune system. When the researchers knocked down MECR in these models, tumor progression was significantly inhibited. Crucially, the suppressed tumors showed increased activation of CD8-positive T cells, the cytotoxic “killer” cells of the adaptive immune system that are responsible for recognizing and destroying cancer cells. This finding positioned MECR not just as a metabolic driver but as a potential architect of immune evasion, reshaping the tumor microenvironment in ways that keep the most potent anti-cancer immune warriors in check.

To confirm that CD8-positive T cells were genuinely responsible for the antitumor effect, the researchers performed an elegant depletion experiment. When they eliminated CD8-positive T cells from the mice, the antitumor benefits of MECR silencing were partially rescued—in other words, tumors grew more effectively again when the killer T cells were absent. This experiment demonstrated that CD8-mediated immunity is a key contributor to the therapeutic effect of suppressing MECR, cementing the link between this metabolic enzyme and the immune response against prostate cancer. The implication is profound: targeting MECR could simultaneously deprive tumors of a metabolic advantage and unleash the immune system against them, a dual mechanism that mirrors the goals of modern combination immunotherapy.

The broader context of this work touches one of the most pressing challenges in prostate cancer treatment. While immune checkpoint inhibitors have revolutionized the treatment of many cancers, prostate cancer has proven remarkably resistant to these therapies, in part because prostate tumors typically foster an immunologically “cold” microenvironment with few active T cells. Understanding how individual metabolic genes remodel this microenvironment could reveal why prostate cancers exclude or suppress immune cells and point to strategies for reversing that process. The authors of the new study frame their findings as a contribution to understanding immune evasion and the therapeutic resistance that flows from it. By integrating tumor-intrinsic mechanisms—proliferation, migration, apoptosis resistance—with immune-associated remodeling, the study offers a more holistic view of how prostate cancer progresses than approaches that examine tumor cells in isolation.

There are also translational implications for prognostic modeling. A three-gene signature that outperforms standard clinical variables would be relatively straightforward to implement in pathology laboratories using routine molecular techniques such as quantitative PCR or RNA sequencing. If validated in prospective clinical cohorts, the MECR-HVCN1-NGFR signature could help clinicians identify patients whose apparent low-risk disease nonetheless carries molecular features of aggressiveness, guiding decisions about active surveillance versus active treatment. Meanwhile, MECR itself, as the sole poor-prognosis gene in the panel and a mechanistically validated driver, stands out as a candidate for drug development. Small molecules targeting mitochondrial fatty acid synthesis enzymes are an emerging area of cancer pharmacology, and this study provides preclinical evidence that such an approach could pay dividends in prostate cancer specifically.

The study was approved by the Ethics Committee of Nanjing Medical University, conducted in accordance with the Declaration of Helsinki with written informed consent from all human participants, and animal experiments complied with institutional ethical regulations and ARRIVE guidelines. The research team, spanning the Affiliated Huaian No. 1 People’s Hospital of Nanjing Medical University, the Affiliated Suzhou Hospital of Nanjing Medical University, and the Second Affiliated Hospital of Soochow University, published the work as an open-access article, making the data freely available to researchers worldwide. As with all preclinical research, the path from laboratory finding to clinical application will require further validation, including studies in larger patient cohorts and the development of pharmacological tools to inhibit MECR in humans. But the convergence of prognostic value, mechanistic clarity, and immune relevance in a single gene is rare in cancer research, and it is precisely this convergence that makes MECR a target worth watching. If future studies confirm these findings, suppressing MECR could become a strategy that attacks prostate cancer on two fronts at once—starving the tumor of its metabolic advantages while stripping away the defenses it uses to hide from the immune system.

The finding matters because prostate tumors are unusually dependent on cholesterol metabolism. Cholesterol is not simply a circulating substance associated with cardiovascular disease; inside a rapidly dividing cancer cell, it serves as a structural component of new membranes and as a precursor for steroid hormones. Prostate cancer cells can synthesize cholesterol internally, import it from the surrounding environment or store it in esterified form for later use. These processes are tightly controlled in healthy tissue, but malignant cells often reprogram them to sustain continuous growth. The new study places propionyl-CoA at an important point in that reprogramming. Produced when isoleucine and valine are broken down, propionyl-CoA normally enters pathways involved in energy production and carbon metabolism. In prostate cancer, however, the researchers’ findings indicate that it can influence the expression or activity of cholesterol-related machinery, effectively linking the availability of specific nutrients to the tumor’s capacity to manufacture and manage lipids.

This is a striking example of metabolic flexibility, the ability of cancer cells to change their preferred fuel sources as conditions shift. Tumors exist in environments where oxygen, glucose and other nutrients may fluctuate, so successful cancer cells frequently build alternative routes for obtaining energy and raw materials. Branched-chain amino acids are especially interesting because they are abundant in the diet and participate in several layers of metabolism. After uptake into cells, isoleucine and valine are converted through a series of enzymatic reactions that remove their amino groups and produce acyl-CoA intermediates. Among those intermediates is propionyl-CoA, which can be further processed through pathways connected to the tricarboxylic acid cycle. The study suggests that, in prostate cancer, propionyl-CoA is not merely burned for energy. Instead, it acts as a metabolic signal or substrate that helps push cholesterol metabolism toward a state favorable to tumor expansion.

The mechanism could help explain why nutrient availability sometimes has effects that are invisible when researchers examine only individual metabolites. A metabolite such as propionyl-CoA can influence cells in several ways at once. It may provide carbon for downstream reactions, alter the balance of competing metabolic pathways or affect protein regulation through chemical modifications. Propionyl-CoA is also related to propionylation, a form of lysine acylation that can modify proteins, including proteins associated with gene control. Such modifications have the potential to change the activity of transcriptional programs without altering the underlying DNA sequence. In the context of prostate cancer, this may help activate genes that support cholesterol synthesis, uptake, transport or storage. The paper’s central message is therefore broader than the effect of two amino acids: it reveals how a nutrient-derived CoA metabolite can connect carbon flow to the regulatory systems that determine whether a cancer cell accumulates the lipids needed for proliferation.

The cholesterol connection is particularly relevant to prostate biology because many prostate tumors remain responsive to androgen signaling, even after treatment. Androgens and other steroid hormones are synthesized from cholesterol-derived precursors, while cholesterol itself supports the organization of cell membranes and signaling platforms. Cancer cells can exploit this relationship by increasing cholesterol production or storage, strengthening pathways that maintain growth signals under therapeutic pressure. The study’s findings suggest that isoleucine and valine may reinforce this metabolic environment by increasing propionyl-CoA-dependent cholesterol activity. That does not mean that eating a single food immediately causes prostate cancer, nor does it establish that eliminating these amino acids from the diet would be safe or effective. Isoleucine and valine are essential nutrients involved in normal muscle maintenance, immune function and tissue repair. The significance lies in how malignant cells use them, not in treating the amino acids as inherently harmful.

The research also raises questions about the relationship between systemic nutrition and the tumor microenvironment. Blood concentrations of nutrients are influenced by diet, exercise, liver and muscle metabolism, kidney function and the overall state of health. Inside a tumor, however, nutrient concentrations can differ substantially from those in circulation. Cancer-associated fibroblasts, immune cells and blood vessels all contribute to the local chemical environment, and metabolites can move between these cell populations. If prostate cancer cells are particularly efficient at converting branched-chain amino acids into propionyl-CoA, they may gain a competitive advantage when those nutrients are available. Conversely, metabolic stress could force tumors to rely more heavily on alternative pathways. Mapping this exchange will be important, because the consequences of nutrient metabolism cannot be understood by studying cancer cells in isolation from the tissues around them.

From a therapeutic perspective, the pathway offers several possible intervention points. Researchers might investigate enzymes that break down isoleucine and valine, proteins that generate or consume propionyl-CoA, and the cholesterol-synthesis or cholesterol-transport systems influenced by the metabolite. Drugs that block cholesterol production already exist, and other treatments target androgen signaling or lipid storage. Combining such approaches with inhibitors of branched-chain amino-acid metabolism could, in principle, deprive prostate cancer cells of both the signal and the raw materials needed to maintain their cholesterol program. But the risks are substantial. The same metabolic enzymes operate in healthy organs, especially skeletal muscle, liver and heart, and broad inhibition could cause toxicity or interfere with normal energy balance. Any treatment strategy would therefore need to distinguish cancer-specific metabolic dependencies from the essential functions of these nutrients throughout the body.

The study points toward a future in which cancer metabolism is analyzed with far greater precision than the familiar labels of “sugar-burning” or “fat-burning.” A tumor may use glucose for one purpose, amino acids for another and lipids for a third, while constantly redirecting intermediates among these networks. In prostate cancer, the isoleucine–valine–propionyl-CoA axis may represent one of those hidden connections, allowing dietary nutrients to influence the production and handling of cholesterol. The next steps will be to determine how broadly this mechanism operates across prostate cancer subtypes, whether it changes during treatment or metastasis, and whether patients with distinct metabolic profiles respond differently to interventions aimed at it. For now, the work delivers a vivid biological warning against simplistic nutritional conclusions: the question is not merely what a cancer patient eats, but how a tumor rewires the chemistry of those nutrients to support its own survival.

Subject of Research: Isoleucine- and valine-driven metabolic regulation of cholesterol metabolism and prostate cancer progression

Article Title: Isoleucine and valine promote prostate cancer progression via propionyl-CoA-mediated cholesterol metabolism

Article References: Li, Z., Liu, S., Jin, W. et al. Isoleucine and valine promote prostate cancer progression via propionyl-CoA-mediated cholesterol metabolism. Nature Metabolism 8, 1772–1790 (2026). https://doi.org/10.1038/s42255-026-01583-z

Image Credits: AI Generated

DOI: 10.1038/s42255-026-01583-z

Keywords: prostate cancer, isoleucine, valine, branched-chain amino acids, propionyl-CoA, cholesterol metabolism, cancer metabolism, tumor progression, lipid metabolism, precision oncology

The central player is propionyl-CoA, a molecule generated when cells break down certain branched-chain amino acids, particularly isoleucine and valine. These essential amino acids cannot be produced by the human body and are obtained through food, including meat, fish, dairy products and other protein-rich sources. Under normal conditions, propionyl-CoA is one intermediate in the metabolism of nutrients for energy and cellular construction. The Weill Cornell team found that, in prostate cancer, the molecule can also function as a signal that changes the behavior of a key regulatory protein.

The investigators began by examining human prostate tumors and discovered elevated levels of propionylcarnitine, a closely related metabolite that reflects propionyl-CoA activity. The metabolite was particularly abundant in more aggressive tumors, providing a clue that the pathway might be associated with disease progression. Further experiments in prostate cancer cells revealed that propionyl-CoA chemically modifies a protein called sterol regulatory element-binding protein 2, or SREBP2. This modification, known as propionylation, stabilizes SREBP2 and keeps it active for longer than it normally would be.

SREBP2 is a master regulator of cholesterol metabolism. In healthy cells, it operates as part of a feedback system: when cholesterol levels fall, SREBP2 enters the nucleus and activates genes involved in cholesterol synthesis and uptake. As cholesterol accumulates, the pathway is normally dampened, preventing excessive production. The new findings indicate that propionyl-CoA can interfere with this metabolic brake. By propionylating SREBP2, the cancer cell effectively keeps its cholesterol-making machinery switched on, even when internal cholesterol levels would ordinarily signal that production should stop.

That sustained cholesterol production may be especially valuable to prostate tumors because cholesterol is not merely a component of cell membranes. It can also serve as a precursor for steroid hormones, including androgens such as testosterone. Androgens activate the androgen receptor, a transcription factor that drives the expression of genes supporting prostate cancer growth and survival. Hormone therapies, including androgen-receptor inhibitors such as enzalutamide, are designed to disrupt this signaling system. However, if tumor cells increase their own supply of cholesterol and use it to generate additional male hormones, they may preserve enough androgen signaling to withstand treatment.

The researchers observed that propionyl-CoA levels increased when prostate cancer cells were deprived of male hormones in laboratory models. This suggests that hormone suppression itself may trigger the metabolic adaptation. Rather than simply becoming starved of a growth signal, the cancer cells appear capable of switching their nutrient-processing priorities, converting amino-acid breakdown into a route for restoring cholesterol and steroid production. The result is a feedback loop in which treatment-induced stress activates a pathway that helps rebuild the very hormonal environment therapy is intended to eliminate.

Experiments in mice provided additional evidence that this pathway can influence tumor behavior. Restricting isoleucine and valine slowed tumor growth and reduced the ability of prostate cancer cells to colonize the lungs. Conversely, increasing propionyl-CoA promoted tumor growth and enhanced lung colonization. These results do not establish that dietary manipulation can treat prostate cancer in people, but they suggest that nutrient availability may influence the metabolic flexibility that allows tumors to become more aggressive. The findings also point toward enzymes involved in converting isoleucine and valine into propionyl-CoA as possible drug targets.

The pathway could have implications beyond amino-acid metabolism. Because it ultimately drives cholesterol synthesis, it may help explain why studies of statins, cholesterol-lowering drugs, have produced mixed results in prostate cancer. If only a subset of tumors relies heavily on propionyl-CoA-driven SREBP2 activation, those tumors might be more vulnerable to interventions that block cholesterol production. Measuring metabolites such as propionylcarnitine, or assessing the activity of the associated enzymes and SREBP2 modification, could eventually help identify patients most likely to benefit from cholesterol-lowering strategies combined with hormone therapy.

The researchers caution that the biology is more complicated than simply removing two amino acids from the diet. Isoleucine and valine are required for normal protein synthesis and other physiological processes, while propionyl-CoA can arise from additional sources within the body. Aging, cancer-associated muscle wasting, obesity and diabetes can all alter amino-acid metabolism and circulating nutrient levels. Whether these systemic changes increase propionyl-CoA production inside human tumors remains unknown. Any dietary intervention would therefore require carefully controlled clinical studies to determine safety, nutritional consequences and whether it improves treatment responses.

The study underscores a growing view of cancer metabolism as a communication system rather than a passive source of energy. Nutrients and their breakdown products can act as molecular messages, changing gene regulation and helping malignant cells adapt to therapy. By connecting branched-chain amino acids to SREBP2, cholesterol production and androgen signaling, the Weill Cornell investigators have identified a potential explanation for how prostate tumors evade hormone deprivation. The next steps will be to test drugs that block the pathway, determine whether dietary strategies can safely influence it, and establish whether the mechanism operates in patients with treatment-resistant disease. If confirmed, a metabolic signal generated from ordinary nutrients could become a new vulnerability in one of the most persistent forms of cancer.

Subject of Research: Prostate cancer metabolism, hormone therapy resistance, branched-chain amino acids, propionyl-CoA, cholesterol synthesis and androgen signaling.

News Publication Date: 20-Aug-2026

Web References: https://mediasvc.eurekalert.org/Api/v1/Multimedia/5a01e294-78ba-4b60-93fd-2713d5b5ac91/Rendition/low-res/Content/Public; https://vivo.weill.cornell.edu/display/cwid-job2064; https://vivo.weill.cornell.edu/display/cwid-zhl4003

Image Credits: Zhongchi Li

Keywords: Prostate cancer, prostate tumors, hormone therapy, enzalutamide, androgen receptor, amino acid metabolism, isoleucine, valine, propionyl-CoA, propionylcarnitine, SREBP2, cholesterol metabolism, cancer metastasis, statins, metabolic therapy.

GDF15’s influence on prostate cancer biology is intricate and often paradoxical, reflecting its capacity to engage multiple cellular and molecular pathways. One of the core functions of GDF15 lies in its capacity to modulate the tumor microenvironment (TME), the complex ecosystem of cancer cells, immune infiltrates, and stromal components. By impairing T cell recruitment and adhesion through inhibition of LFA-1/β2-integrin–mediated interactions with activated endothelial cells, GDF15 effectively dampens anti-tumor immune responses, fostering an immunosuppressive “cold” milieu that enables tumor evasion from immune surveillance. This immunomodulatory effect extends further, as GDF15 hinders the infiltration of dendritic cells and granulocytes and activates M2 macrophages, which are known for their tumor-promoting activities.

Beyond immune escape, GDF15 actively shapes the stromal compartment, orchestrating the transformation of cancer-associated fibroblasts (CAFs) into myofibroblast phenotypes known for their enhanced collagen production. This remodeling contributes to increased tumor stiffness and facilitates invasive cancer cell behavior. Interestingly, fibroblasts themselves are a significant source of GDF15, perpetuating a feed-forward loop that exacerbates tumor progression. Such dual roles exemplify the contextual nature of GDF15 function, which, while generally pro-tumorigenic, can under certain conditions limit local tumor growth via mechanisms dependent on cytotoxic CD8⁺ T cells, even as it paradoxically promotes distant metastatic spread.

Metastatic dissemination to bone is a hallmark of advanced prostate cancer and a major contributor to morbidity and mortality. GDF15 is integral to establishing a metastatic niche within the rigid bone microenvironment. It enhances osteoblast activity and drives the secretion of chemokines like CCL2 and receptor activator of nuclear factor kappa-B ligand (RANKL), pivotal factors for osteoclast recruitment and activation. This cascade accelerates osteoclastogenesis, the bone-resorbing process that creates space for metastatic colonization and tumor growth. Through this bone stromal remodeling, GDF15 not only supports metastatic establishment but also fosters the vicious cycle of bone degradation and tumor expansion characteristic of skeletal metastases in prostate cancer.

The challenge of chemoresistance in advanced prostate cancer, particularly resistance to frontline agents such as docetaxel, remains a primary barrier to durable therapeutic responses. Emerging evidence identifies GDF15 as a salient mediator of this resistance. Elevated expression of GDF15 has been documented in docetaxel-resistant prostate cancer cell lines, where it functions as a cytoprotective factor enabling tumor cells to withstand chemotherapy-induced cytotoxicity. Functional studies reveal that knocking out GDF15 in resistant cells restores sensitivity to docetaxel, underscoring its central role in modulating drug response. These insights propel GDF15 to the forefront as a promising target to overcome chemoresistance and improve treatment outcomes.

Clinically, GDF15 holds significant promise beyond therapeutic targeting. Its role as a biomarker in prostate cancer diagnosis and prognosis is gaining traction. Unlike the prostate-specific antigen (PSA), which suffers from limited tumor specificity and frequent false-positive results, serum GDF15 levels exhibit distinct patterns reflecting disease status. Lower levels are typically observed in localized prostate cancer, whereas markedly elevated levels correlate with metastatic disease. Incorporating GDF15 measurements enhances diagnostic precision; for instance, the MIC-PSA algorithm, integrating GDF15 with PSA, improves cancer detection accuracy and holds the potential to reduce unnecessary biopsies by approximately 27%.

Further refining risk stratification, combinatorial biomarker panels including GDF15 offer superior predictive power for distinguishing aggressive low-risk prostate cancers. Additionally, elevated GDF15 independently predicts worse cancer-specific survival and discriminates lethal from indolent localized disease, positioning it as a clinically valuable prognostic tool. Such applications pave the way for more personalized patient management, guiding decisions on intervention intensity and surveillance.

Perhaps the most exciting frontier lies in therapeutically targeting the GDF15 pathway. Several monoclonal antibodies currently in clinical development aim to neutralize GDF15 signaling and its downstream effects. AV-380, an inhibitory antibody, has demonstrated promising preclinical efficacy in reversing cachexia-related phenotypes by restoring weight, muscle mass, and fat reserves. NGM120, an antagonist of the GDF15 receptor GFRAL, has shown encouraging anti-cancer activity in early-phase clinical trials involving advanced prostate cancer patients, with reported cases of partial tumor responses. Another agent, Visugromab, exhibits potential for synergistic enhancement of immunotherapy by neutralizing GDF15, thereby facilitating immune cell infiltration and improving the effectiveness of PD-1/PD-L1 checkpoint blockade therapies.

Other candidates, such as Ponsegromab and AZD8853, further expand the therapeutic arsenal targeting GDF15-related pathways, with ongoing trials evaluating their roles in treating cancer cachexia and potentially overcoming resistance to immunotherapy. Collectively, these advances highlight the therapeutic versatility of targeting GDF15, addressing both tumor intrinsic mechanisms and systemic effects that compromise patient health.

The multifactorial role of GDF15 in prostate cancer—from modulating the immune milieu and stromal dynamics to driving bone metastasis and mediating chemoresistance—affirms its status as a complex molecular node ripe for precision interventions. Its dualistic functions necessitate nuanced understandings of context-dependent effects but also present multiple therapeutic entry points. As research progresses, integrating GDF15-centered strategies promises to transform prostate cancer management, potentially improving survival rates and quality of life for millions affected by this devastating disease.

In conclusion, the evolving landscape of prostate cancer biology now recognizes GDF15 as a linchpin molecule orchestrating critical aspects of tumor progression, metastasis, cachexia, and resistance to therapy. The convergence of mechanistic insights and translational applications—from diagnostic biomarkers to monoclonal antibody therapies—portends a new era where precision targeting of GDF15 may redefine clinical paradigms in prostate cancer treatment. Ongoing and future trials will elucidate the full therapeutic potential of this compelling target, offering hope for enhanced efficacy and patient outcomes.

Subject of Research: Growth Differentiation Factor 15 (GDF15) in Prostate Cancer

Article Title: Decoding GDF15: Impact on prostate cancer metabolism, chemoresistance, and clinical applications

News Publication Date: 24-Nov-2025

Web References: http://dx.doi.org/10.1097/CM9.0000000000003876

References: DOI: 10.1097/CM9.0000000000003876

Image Credits: Chinese Medical Journal

Keywords: Prostate cancer, GDF15, tumor microenvironment, bone metastasis, chemoresistance, immunosuppression, cachexia, targeted therapy, biomarkers, monoclonal antibodies