Radiosensitizing Favors Response to Peptide Receptor Radionuclide Therapy in Patients With Highly Proliferative Neuroendocrine Malignancies: Preliminary Evidence From a Clinical Pilot Study.

AIM/INTRODUCTION: Peptide receptor radionuclide therapy (PRRT) represents a cornerstone of treatment regimens for patients with low proliferative neuroendocrine tumors (NETs). However, in patients experiencing somatostatin receptor-positive NET with higher proliferation rates, a value and potential therapeutic benefit of PRRT as part of multimodal treatment approaches and potentially with addition of radiosensitizing agents has not yet been established. PATIENTS AND METHODS: In this study, 20 patients with histologically confirmed gastroenteropancreatic (GEP) NET with proliferation rates (Ki67) between 15% and 55% were treated either with PRRT only (n = 10) or with a combination therapy (n = 10) comprising PRRT and capecitabine/temozolomide (CAP/TEM) for at least 2 consecutive cycles. RESULTS: Disease control rate in patients treated with PRRT alone was 60% (40% stable disease and 20% partial response). Strikingly, in patients treated with PRRT in combination with radiosensitization (CAP/TEM), the disease control rate was 90% (20% stable disease and 70% partial response). The median progression-free survival in the PRRT only group was 12 months, whereas the median progression-free survival in the PRRT + CAP/TEM group was 26 months and has not been yet reached for all patients in the group during the observation period. The median disease-specific survival for patients with PRRT alone was 51 months, whereas this end point was not yet reached in the PRRT + CAP/TEM group. Moreover, the PRRT + CAP/TEM group showed a significantly higher reduction of SSTR-PET-based metabolic tumor volume and chromogranin A levels compared with the PRRT only group. Importantly, adverse events of all grades did not differ between both groups. CONCLUSIONS: PRRT + CAP/TEM represents a highly promising and well-tolerated therapeutic regimen for patients experiencing somatostatin receptor-positive NET with higher (Ki67 ≥ 15%) proliferation rate. Prospective randomized clinical trials are warranted.

Myasthenia gravis as initial presentation of a pancreatic neuroendocrine tumor: A case report.

Myasthenia gravis (MG) is a heterogeneous autoimmune disease, which is characterized by a postsynaptic neuromuscular transmission defect, with antibodies directly targeting the acetylcholine receptor (AChR) or other structural proteins of the neuromuscular junction. The majority of MG cases are associated with thymic pathologies, including thymoma, thyroiditis, autoimmune diseases or malignant hematologic neoplasia. The present study reported a rare case of AChR-positive and late-onset ocular MG, which rapidly progressed to a generalized myasthenic syndrome as an initial presentation of a pancreatic neuroendocrine neoplasia (pNEN). Following complete surgical resection of the pNEN, the myasthenic syndrome was improved and the anti-AChR antibody titers were reduced. It has been reported that MG is a paraneoplastic syndrome in thymic neoplasms and less common in hematologic malignancies. However, currently, only few cases of MG as initial presentation of a solid tumor, and more particular of a neuroendocrine neoplasm, have been reported in the literature. In conclusion, surveillance for extrathymic solid malignancies in newly diagnosed patients with MG could promote the early diagnosis of associated tumor diseases.

Diagnostic Approaches for Neuroendocrine Neoplasms of Unknown Primary (NEN-UPs) and Their Prognostic Relevance-A Retrospective, Long-Term Single-Center Experience.

Neuroendocrine neoplasms (NENs) represent a rare and heterogenous group of tumors with predominantly gastroenteropancreatic or pulmonary origin. Despite numerous diagnostic efforts, the primary tumor site remains unknown in up to 20% of the patients diagnosed with NEN. In this subgroup of NEN patients, a standard diagnostic algorithm has not yet been integrated into clinical routine. Of note, an undetermined primary tumor site in NENs is associated with an impaired clinical outcome by at least "formally" limiting treatment options exclusively approved for NENs of a certain histological origin. In this retrospective study, a patient cohort of 113 patients initially diagnosed with NEN of unknown primary (NEN-UP) was analyzed. In 13 patients (11.5%) a primary tumor site could be identified subsequently, amongst others, by performing somatostatin receptor (SSTR)-PET-based imaging, which was irrespective of the initial clinical or demographic features. Diagnostic work-up and therapeutic regimens did not differ significantly between patients with an identified or unidentified primary tumor site; only a detailed immunohistochemical assessment providing additional information on the tumor origin proved to be significantly associated with the detection of a primary tumor site. Our study revealed that a profound diagnostic work-up, particularly including SSTR-PET-based imaging, leads to additional treatment options, finally resulting in significantly improved clinical outcomes for patients with NEN-UPs.

Long-term prognostic factors for PRRT in neuroendocrine tumors.

Aim/introduction: Peptide receptor radionuclide therapy (PRRT) is an effective and well-tolerated treatment option for patients with neuroendocrine tumors (NETs) that prolongs progression-free survival (PFS). However, the limited overall survival (OS) rates in the prospective phase III study (NETTER1) highlighted the need to identify patient-specific long-term prognostic markers to avoid unnecessary side effects and enable better treatment stratification. Therefore, we retrospectively analyzed prognostic risk factors in NET patients treated with PRRT. Methods: A total of 62 NET patients (G1: 33.9%, G2 62.9%, and G3 3.2%) with at least 2 cycles of PRRT with [177Lu]Lu-HA-DOTATATE (mean 4 cycles) were analyzed. Of which, 53 patients had primary tumors in the gastroenteropancreatic (GEP) system, 6 had bronchopulmonary NET, and 3 had NET of unknown origin. [68Ga]Ga-HA-DOTATATE PET/CT scans were performed before PRRT start and after the second treatment cycle. Different clinical laboratory parameters, as well as PET parameters, such as SUVmean, SUVmax, and PET-based molecular tumor volume (MTV), were collected, and their impact on the OS was investigated. Patient data with a mean follow-up of 62 months (range 20-105) were analyzed. Results: According to interim PET/CT, 16 patients (25.8%) presented with partial response (PR), 38 (61.2%) with stable disease (SD), and 7 (11.3%) with progressive disease (PD). The 5-year OS was 61.8% for all patients, while bronchopulmonary NETs showed poorer OS than GEP-NETs. Multivariable Cox regression analysis showed that chromogranin A level and MTV together were highly significant predictors of therapeutic outcome (HR 2.67; 95% CI 1.41-4.91; p = 0.002). Treatment response was also influenced by the LDH level (HR 0.98; 95% CI 0.9-1.0; p = 0.007) and patient age (HR 1.15; 95% CI 1.08-1.23; p < 0.001). ROC analysis revealed baseline MTV > 112.5 ml [Sens. 91%; Spec. 50%; AUC 0.67 (95% CI 0.51-0.84, p = 0.043)] and chromogranin A >1,250.75 µg/l [Sens. 87%; Spec. 56%; AUC 0.73 (95% CI 0.57-0.88, p = 0.009)] as the best cutoff values for identifying patients with worse 5-year survival. Conclusion: Our retrospective analysis defined MTV and chromogranin A in combination as significant prognostic factors for long-term OS. Furthermore, an interim PET/CT after two cycles has the potential in identifying non-responders who may benefit from a change in therapy at an early stage.

NOTCH3 missense mutations as predictor of long-term response to gemcitabine in a patient with epithelioid hemangioendothelioma.

PURPOSE: Epithelioid hemangioendothelioma (EHE) as a very rare malignant vascular tumor belongs to the heterogenous group of soft-tissue sarcomas. Depending on the clinical course of the disease, interdisciplinary treatment concepts are required, including surgery, radiotherapy and systemic cancer therapy. However, due to its uncommonness, standard treatment options are lacking so far, especially in advanced disease with distant metastases. METHODS AND RESULTS: Here we report on an unusual case of a patient with metastasized EHE showing long-term response to second line treatment with gemcitabine over almost 2 decades. Cancer genome sequencing of the patient's tumor tissue detected a NOTCH3 missense mutation which could provide an explanation for these clinical findings. NOTCH3 is known to be a mediator of resistance towards gemcitabine-based cancer treatment, at least in pancreatic cancer and non-small cell lung cancer. CONCLUSION: The observation that this missense mutation of NOTCH3 is associated with an increased response to treatment with gemcitabine in EHE can be used prospectively to assess NOTCH3 as potential biomarker for predicting therapy response to gemcitabine.

Treatment modalities favoring outcome in well-differentiated neuroendocrine tumors G3.

Introduction: Neuroendocrine neoplasms (NEN) are a rare and heterogenous group of tumors arising from neuroendocrine cells in multiple organs. Neuroendocrine tumors (NET) G3 encompass a small subgroup accounting for less than 10% of all neuroendocrine neoplasms. In contrast to NET G1 and G2 as well as neuroendocrine carcinomas (NEC), in NET G3 data on treatment and patient outcomes are still limited. Especially in a metastasized tumor stage, the role of surgery, peptide receptor radionucleotide therapy (PRRT), and systemic chemotherapy is not clearly defined. Methods: In this real-life cohort, we consecutively analyzed clinical outcome in NET G3 patients receiving different diagnostic and treatment. Results and discussion: We found that even metastasized NET G3 patients undergoing surgery, or receiving radiation, somatostatin analogues (SSA), and PRRT showed a clear survival benefit. Interestingly, all treatment regimen were superior to classical chemotherapeutic agents. In addition, somatostatin receptor (SSTR) PET-CT, FDG PET-CT, and repetitive biopsies were shown to be useful diagnostic and prognostic tools in NET G3. Our study demonstrates that patients with highly proliferative NET G3 might benefit from less aggressive treatment modalities commonly used in low proliferative NEN.

Inflammatory Surrogate Parameters for Predicting Ifosfamide-Induced Neurotoxicity in Sarcoma Patients.

Sarcomas compromise a heterogenous group of tumors of a mesenchymal origin. Although treatment options in many solid tumors have evolved over the past decades, the treatment of advanced sarcoma is still based on conventional chemotherapeutic agents. Beside anthracyclines, alkylating agents such as ifosfamide are frequently used in sarcoma treatment. However, treatment with ifosfamide can cause severe dose- and treatment-limiting side effects, such as ifosfamide-induced neurotoxicity (IIN). Especially in sarcoma, consecutive risk assessment analyses investigating the individual factors associated with the increased incidence in IIN, remain insufficient so far. In this retrospective analysis, we investigated 172 sarcoma patients treated with ifosfamide. Out of 172 patients, 49 patients (28.5%) developed IIN. While gender, age, histologic origin, and tumor stage were not associated with the occurrence of IIN, infusion times, simultaneous radiotherapy, and concomitant use of opioids or anticonvulsants affected the risk of developing IIN. Sarcoma patients with IIN showed an alteration in several inflammatory markers, including a lower lymphocyte count, hemoglobin levels, and calcium levels, as well as elevated GGT, sodium, and CRP levels. Remarkably, the occurrence of IIN was associated with a worse prognosis regarding progression free and overall survival. In addition, high CTCAE grades were negatively associated with overall survival in sarcoma. The observation that an inflammatory state is associated with an increased risk of IIN in sarcoma patients can be used prospectively to further investigate the relationship of inflammation and IIN. In addition, the easily accessible blood markers used in our study to predict IIN can be incorporated into clinical decision making.

NUT Carcinoma-An Underdiagnosed Malignancy.

NUT carcinoma (NC) is a rare and highly aggressive malignancy with a dismal prognosis and a median survival of 6-9 months only. Although very few cases of NC are reported each year, the true prevalence is estimated to be much higher, with NC potentially widely underdiagnosed due to the lack of awareness. NC primarily occurs in midline structures including thorax, head, and neck; however, other sites such as pancreas and kidney are also affected, albeit at lower frequencies. NC is characterized by a single translocation involving the NUTM1 (NUT midline carcinoma family member 1) gene and different partner genes. The resulting fusion proteins initiate tumorigenesis through a mechanism involving BET (bromo-domain and extra-terminal motif) proteins such as Bromodomain-containing protein 4 (BRD4) and inordinate acetylation of chromatin, leading to the dysregulation of growth and differentiation genes. While no clinical characteristics are specific for NC, some histologic features can be indicative; therefore, patients with these tumor characteristics should be routinely tested for NUTM1. The diagnosis of NC using immunohistochemistry with a highly specific antibody is straightforward. There are currently no standard-of-care treatment options for patients with NC. However, novel therapies specifically addressing the unique tumorigenic mechanism are under investigation, including BET inhibitors. This review aims to raise awareness of this underdiagnosed cancer entity and provide all patients the opportunity to be properly diagnosed and referred to a clinical study.

Controversial Role of the Immune Checkpoint OX40L Expression on Platelets in Breast Cancer Progression.

In conventional T cells, OX40 has been identified as a major costimulating receptor augmenting survival and clonal expansion of effector and memory T cell populations. In regulatory T cells, (Treg) OX40 signaling suppresses cellular activity and differentiation. However, clinical trials investigating OX40 agonists to enhance anti-tumor immunity, showed only limited success so far. Here we show that platelets from breast cancer patients express relevant levels of OX40L and platelet OX40L (pOX40L) inversely correlates with platelet-expressed immune checkpoint molecules GITRL (pGITRL) and TACI (pTACI). While high expression of pOX40L correlates with T and NK cell activation, elevated pOX40L levels identify patients with higher tumor grades, the occurrence of metastases, and shorter recurrence-free survival (RFS). Of note, OX40 mRNA levels in breast cancer correlate with enhanced expression of anti-apoptotic, immune-suppressive, and tumor-promoting mRNA gene signatures. Our data suggest that OX40L on platelets might play counteracting roles in cancer and anti-tumor immunity. Since pOX40L reflects disease relapse better than the routinely used predictive markers CA15-3, CEA, and LDH, it could serve as a novel biomarker for refractory disease in breast cancer.

Early Reconstitution of Antibody Secreting Cells after Allogeneic Stem Cell Transplantation.

Immune cell reconstitution after stem cell transplantation is allocated over several stages. Whereas cells mediating innate immunity recover rapidly, adaptive immune cells, including T and B cells, recover slowly over several months. In this study we investigated kinetics and reconstitution of de novo B cell formation in patients receiving CD3 and CD19 depleted haploidentical stem cell transplantation with additional in vivo T cell depletion with monoclonal anti-CD3 antibody. This model enables a detailed in vivo evaluation of hierarchy and attribution of defined lymphocyte populations without skewing by mTOR- or NFAT-inhibitors. As expected CD3+ T cells and their subsets had delayed reconstitution (<100 cells/µL at day +90). Well defined CD19+ B lymphocytes of naïve and memory phenotype were detected at day +60. Remarkably, we observed a very early reconstitution of antibody-secreting cells (ASC) at day +14. These ASC carried the HLA-haplotype of the donor and secreted the isotypes IgM and IgA more prevalent than IgG. They correlated with a population of CD19- CD27- CD38low/+ CD138- cells. Of note, reconstitution of this ASC occurred without detectable circulating T cells and before increase of BAFF or other B cell stimulating factors. In summary, we describe a rapid reconstitution of peripheral blood ASC after CD3 and CD19 depleted haploidentical stem cell transplantation, far preceding detection of naïve and memory type B cells. Incidence before T cell reconstitution and spontaneous secretion of immunoglobulins allocate these early ASC to innate immunity, eventually maintaining natural antibody levels.

Platelet PD-L1 reflects collective intratumoral PD-L1 expression and predicts immunotherapy response in non-small cell lung cancer.

Immune-checkpoint inhibitors (ICI) have transformed oncological therapy. Up to 20% of all non-small cell lung cancers (NSCLCs) show durable responses upon treatment with ICI, however, robust markers to predict therapy response are missing. Here we show that blood platelets interact with lung cancer cells and that PD-L1 protein is transferred from tumor cells to platelets in a fibronectin 1, integrin α5ß1 and GPIbα-dependent manner. Platelets from NSCLC patients are found to express PD-L1 and platelet PD-L1 possess the ability to inhibit CD4 and CD8 T-cells. An algorithm is developed to calculate the activation independent adjusted PD-L1 payload of platelets (pPD-L1Adj.), which is found to be superior in predicting the response towards ICI as compared to standard histological PD-L1 quantification on tumor biopsies. Our data suggest that platelet PD-L1 reflects the collective tumor PD-L1 expression, plays important roles in tumor immune evasion and overcomes limitations of histological quantification of often heterogeneous intratumoral PD-L1 expression.

Significance and clinical impact of routinely tested urinary ethyl glucuronide after liver transplantation - development of a risk score.

Alcohol abuse after liver transplantation can seriously impact graft and patient survival. However, to date, there is no defined standard procedure to identify patients consuming alcohol after liver transplantation. The aim of this study was to analyze the diagnostic value and clinical impact of routinely measured urinary ethyl glucuronide (uEtG) - a metabolite of ethanol - in patients after liver transplantation. Data of 362 consecutive patients after liver transplantation who visited the University Hospital of Tuebingen for outpatient follow-up were analyzed. Forty-eight patients (13%) displayed positive uEtG results. The uEtG positive group contained significantly more patients with pretransplant alcoholic liver disease. However, two thirds of the uEtG positive patients had no history of pretransplant alcoholic liver disease. Several clinical parameters were significantly associated with positive uEtG. In order to enable a more cost-effective application of uEtG in the future, a clinical risk score was developed (specificity 0.95). In conclusion, routine testing for uEtG reveals a considerable percentage of patients practicing alcohol intake after liver transplantation. Application of our proposed risk score could help focusing uEtG testing on patients at risk.

Regulation of Platelet-Derived ADAM17: A Biomarker Approach for Breast Cancer?

Tumor progression and metastasis are critically dependent on the tumor microenvironment. A disintegrin and metalloproteinase 17 (ADAM17) is associated with shedding of several substrates involved in tumor progression and known to be expressed by platelets of healthy donors and patients with solid tumors. Here, we report that platelet-derived ADAM17 (pADAM17) is regulated upon platelet activation of breast cancer patients, but not of healthy individuals. The observed downregulation of pADAM17 on platelets of cancer patients correlated with clinical parameters related to tumor progression including tumor stage and the occurrence of metastasis. Our data identify an association between platelet activation, modulation of platelet-derived ADAM17, and metastasis. In conclusion, we demonstrate that further development of pADAM17 as a liquid biomarker is warranted for monitoring disease progression in breast cancer.

Platelet-Expressed Synaptophysin (pSyn) as Novel Biomarker in Neuroendocrine Malignancies.

Neuroendocrine neoplasms (NENs) encompass a heterogeneous group of tumors. Whereas low-grade neuroendocrine tumors (NETs) are histologically well-differentiated, highly aggressive neuroendocrine carcinomas (NECs) are characterized by a high proliferation rate and a worse clinical outcome. Since most NEN patients need monitoring of tumor progress and response to treatment for a long period of time, especially in metastatic disease, reliable, dynamic, and easy-to-assess biomarkers are needed. In this prospective study, we identified platelet-expressed synaptophysin (pSyn) as a novel biomarker in NENs. The level of pSyn in NENs was significantly upregulated compared to healthy donors. pSyn was positively correlated with higher tumor stages, the occurrence of metastasis, histological grading, and higher tumor proliferation (Ki67). Most importantly, high pSyn expression in our NEN cohort was shown to predict shorter progression-free survival (PFS). In conclusion, our data highlight the potential of pSyn as a novel biomarker in NENs reflecting tumor stages, grading, and prognosis.

Platelet-Expressed TNFRSF13B (TACI) Predicts Breast Cancer Progression.

Although treatment options in breast cancer have been improved significantly, predictive biomarkers for disease progression and metastasis are still lacking. Recent studies indicate that several TNF Receptor Superfamily members are involved in breast cancer cell proliferation and survival. Interestingly, TNFRSF13B (TACI) mRNA level were of prognostic relevance in breast cancer patients. In this study we provide evidence for TACI expression on platelets of breast cancer patients. The level of platelet-expressed TACI (pTACI) was significantly increased on platelets derived from breast cancer patients compared to healthy controls. Upon platelet activation, pTACI was downregulated on the platelet surface of healthy donors and breast cancer patients. Of note, inhibition of matrix metalloprotease (MMP) prevented downregulation of pTACI ex vivo, indicating that proteolytic cleavage of pTACI is responsible for reduction of pTACI level. Stimulation of pTACI via BAFF, BAFF 60-mer or APRIL did not influence platelet activation and function. Remarkably, pTACI was particularly regulated during tumor progression in our breast cancer cohort. TACI expression levels on platelets were correlated with clinical parameters including tumor stage, occurrence of metastasis and tumor cell proliferation (Ki67). In conclusion, our data emphasize the potential use of platelets as a liquid biomarker in breast cancer.

Differences Between CT-Perfusion and Biphasic Contrast-enhanced CT for Detection and Characterization of Hepatocellular Carcinoma: Potential Explanations for Discrepant Cases.

AIM: To compare the diagnostic value of liver perfusion computed tomography (PCT) and biphasic contrast-enhanced CT (bpCECT) for detection and characterization of hepatocellular carcinoma (HCC), and to identify potential causes for inter-modal discrepancies. PATIENTS AND METHODS: In this retrospective study, 162 cases with a total of 325 HCC-typical lesions were evaluated using both PCT and bpCECT (mean time between examinations=15 days, range=0-13 days). HCC diagnosis was performed by multi-modality imaging including lesion growth at follow-up. For PCT, a total acquisition time of 40 s (26 measurements) each 1.5 s using 80 kV and 100 mAs, as well as 50 ml iodine contrast agent (at 5 ml/s) covering the entire liver was used. Mean arterial liver perfusion (ALP), portal venous perfusion (PVP) and hepatic arterial index (HPI) for both tumor and non-involved liver parenchyma; mean blood flow, blood volume and k-trans for tumor were quantified. Tumor localization, and size were registered. bpCECT consisted of unenhanced, arterial (30-33 s delay), and portal-venous (70-75 s) phases performed using 120 kV, 200-250 mAs, thin-slice reformates (<1 mm), 100 ml contrast agent (at 3 ml/s) followed by 50 ml saline flush. Finally, we divided the results according to detection by PCT only (i.e. missed by pbCECT), and by both PCT and pbCECT. RESULTS: PCT detected 272 lesions compared to 217 with bpCECT only. HCCs in liver segments 4 and 5 were significantly better detected by PCT (p<0.005). Furthermore, PCT detected significantly smaller HCCs than did bpCECT (p<0.001). Lesions detected by both methods had significantly higher mean ALP (p=0.03) and HPI (p=0.02), and lower mean PVP (p=0.01). Tumor blood flow, blood volume and k-trans proved not to be significant for lesion detection. The mean ALP, HPI, and PVP in inconspicuous cirrhotic liver were also not significant for lesion detection. The PVP(tumor)/HPI(liver) ratio of detected lesions was significantly higher for PCT alone (p=0.04). Pretreated, still vital lesions were better detected by bpCECT. CONCLUSION: Detection of smaller HCC lesions, lesions located in liver segments 4 and 5, as well as lesions presenting lower ALP and HPI, and higher PVP(tumor)/HPI(liver) ratio was better using both methods, emphasizing the important role of PCT.

Platelet-expressed immune checkpoint regulator GITRL in breast cancer.

Owing to their key role in several diseases including cancer, activating and inhibitory immune checkpoint molecules are increasingly exploited as targets for immunotherapy. Recently, we demonstrated that platelets, which largely influence tumor progression and immune evasion, functionally express the ligand of the checkpoint molecule GITR. This immunoreceptor modulates effector functions of T cells and NK cells with its function varying dependent on cellular context and activation state. Here, we provide a comparative analysis of platelet-derived GITRL (pGITRL) in breast cancer patients and healthy volunteers. The levels of pGITRL were found to be higher on platelets derived from cancer patients and appeared to be specifically regulated during tumor progression as exemplified by several clinical parameters including tumor stage/grade, the occurrence of metastases and tumor proliferation (Ki67) index. In addition, we report that pGITRL is upregulated during platelet maturation and particularly induced upon exposure to tumor-derived soluble factors. Our data indicate that platelets modulate the GITR/GITRL immune checkpoint in the context of malignant disease and provide a rationale to further study the GITR/GITRL axis for exploitation for immunotherapeutic intervention in cancer patients.

Long-term remission of small cell lung cancer after reactivation of tuberculosis following immune-checkpoint blockade: A case report.

Immune-checkpoint inhibitors (ICIs) provide a promising treatment option for advanced tumors including small cell lung cancer (SCLC). Nevertheless, in addition to immune-related adverse events (irAEs), an increased risk of infection including tuberculosis has been previously described. Here, we report a case of long-term remission of a patient with SCLC after reactivation of lung tuberculosis following ICI therapy. Our case illustrates the complexity of ICI-associated immune modulation in tuberculosis. Since new lesions in lung cancer patients are commonly associated with tumor progression, infections with mycobacterial tuberculosis may be underdiagnosed in lung cancer.

LXRα activation and Raf inhibition trigger lethal lipotoxicity in liver cancer.

The success of molecular therapies targeting specific metabolic pathways in cancer is often limited by the plasticity and adaptability of metabolic networks. Here we show that pharmacologically induced lipotoxicity represents a promising therapeutic strategy for the treatment of hepatocellular carcinoma (HCC). LXRα-induced liponeogenesis and Raf-1 inhibition are synthetic lethal in HCC owing to a toxic accumulation of saturated fatty acids. Raf-1 was found to bind and activate SCD1, and conformation-changing DFG-out Raf inhibitors could disrupt this interaction, thereby blocking fatty acid desaturation and inducing lethal lipotoxicity. Studies in genetically engineered and nonalcoholic steatohepatitis-induced HCC mouse models and xenograft models of human HCC revealed that therapies comprising LXR agonists and Raf inhibitors were well tolerated and capable of overcoming therapy resistance in HCC. Conceptually, our study suggests pharmacologically induced lipotoxicity as a new mode for metabolic targeting of liver cancer.