Publications by authors named "Kian-Huat Lim"

Pancreatic ductal adenocarcinoma (PDAC) is a lethal malignancy that is often resistant to therapy. An immune suppressive tumor microenvironment (TME) and oncogenic mutations in have both been implicated as drivers of resistance to therapy. Mitogen-activated protein kinase (MAPK) inhibition has not yet shown clinical efficacy, likely because of rapid acquisition of tumor-intrinsic resistance.

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Autosomal dominant optic atrophy (ADOA) is an inherited optic neuropathy most frequently associated with mutations. Most variants result in haploinsufficiency, and patient cells express roughly half of the normal levels of OPA1 protein. OPA1 is a mitochondrial GTPase that is essential for normal mitochondrial function.

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  • * The research identified TRIM4 as the E3 ligase responsible for TPL2's degradation and showed that certain TPL2 mutants are less stable due to reduced TRIM4 binding.
  • * Mutant KRAS enhances TPL2's stability and activity by degrading TRIM21 and TRIM4, leading to activation of the Wnt signaling pathway, highlighting the potential for TPL2 inhibitors in treating KRAS-mutant cancers.
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How the oncogene drives cancer growth remains poorly understood. Therefore, we established a systemwide portrait of KRAS- and extracellular signal-regulated kinase (ERK)-dependent gene transcription in KRAS-mutant cancer to delineate the molecular mechanisms of growth and of inhibitor resistance. Unexpectedly, our KRAS-dependent gene signature diverges substantially from the frequently cited Hallmark KRAS signaling gene signature, is driven predominantly through the ERK mitogen-activated protein kinase (MAPK) cascade, and accurately reflects KRAS- and ERK-regulated gene transcription in KRAS-mutant cancer patients.

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Targeting the mitogen-activated protein kinase (MAPK) cascade in pancreatic ductal adenocarcinoma (PDAC) remains clinically unsuccessful. We aim to develop a MAPK inhibitor-based therapeutic combination with strong preclinical efficacy. Utilizing a reverse-phase protein array, we observe rapid phospho-activation of human epidermal growth factor receptor 2 (HER2) in PDAC cells upon pharmacological MAPK inhibition.

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Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive and treatment-refractory malignancies. The lack of an effective screening tool results in the majority of patients being diagnosed at late stages, which underscores the urgent need to develop more sensitive and specific imaging modalities, particularly in detecting occult metastases, to aid clinical decision-making. The tumor microenvironment of PDAC is heavily infiltrated with myeloid-derived suppressor cells (MDSCs) that express C-C chemokine receptor type 2 (CCR2).

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Unlabelled: Current treatment approaches for renal cell carcinoma (RCC) face challenges in achieving durable tumor responses due to tumor heterogeneity and drug resistance. Combination therapies that leverage tumor molecular profiles could offer an avenue for enhancing treatment efficacy and addressing the limitations of current therapies. To identify effective strategies for treating RCC, we selected ten drugs guided by tumor biology to test in six RCC patient-derived xenograft (PDX) models.

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  • Researchers identified 25 different cell states, focusing on those linked to aggressive disease and poor prognosis, including specific immune cells and cancer-associated fibroblasts (CAFs).
  • The findings highlight the relationship between the composition of the TME, stemness in malignant cells and CAFs, and patient survival, suggesting potential for improved risk assessment and personalized treatment strategies.
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Purpose: Vitamin D analogues remodel the desmoplastic stroma, and improve vascularity and efficacy of chemotherapy in preclinical pancreas cancer models.

Patients And Methods: We conducted a pilot study to evaluate the safety and preliminary efficacy of the vitamin D analogue paricalcitol in combination with nanoliposomal irinotecan (Nal-iri) plus 5-fluorouracil/leucovorin (5-FU/LV) in patients with advanced pancreatic cancer who had progressed on gemcitabine-based therapy. Two dose levels (DL) of paricalcitol were tested: fixed dose weekly (75 mcg, DL1) and weight-based weekly (7 mcg/kg, /DL2).

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Background: Pancreatic ductal adenocarcinoma (PDAC) is a lethal malignancy. Thus, there is an urgent need for safe and effective novel therapies. PDAC's excessive reliance on glucose metabolism for its metabolic needs provides a target for metabolic therapy.

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Neoantigen burden and CD8 T cell infiltrate are associated with clinical outcome in pancreatic ductal adenocarcinoma (PDAC). A shortcoming of many genetic models of PDAC is the lack of neoantigen burden and limited T cell infiltrate. The goal of the present study was to develop clinically relevant models of PDAC by inducing cancer neoantigens in KP2, a cell line derived from the KPC model of PDAC.

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Evidence-based medicine utilizes research evidence from clinical trials to support treatment decisions. To leverage the advantage of electronic health records and big data analysis methods, we developed a data-driven analytic pipeline that uses 1) agglomerative hierarchical clustering to define different granularity of treatment variation, 2) feature selection and multinomial multivariate logistic regression analysis to identify variables (factors) associated with treatment variation, and 3) prognosis analysis to compare patient outcome across top treatment groups. We tested our approach on the diffuse large B-cell lymphoma patient population from the MIMIC-IV dataset and found that our approach helps determine the optimal granularity of treatment variation and identify factors associated with treatment variation but not realized in randomized controlled trials due to unbalanced patient cohorts.

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  • The study aimed to evaluate the effectiveness, safety, and maximum tolerated dose (MTD) of palbociclib combined with nab-paclitaxel for treating advanced pancreatic ductal adenocarcinoma (PDAC).
  • Preclinical tests showed that this combination outperformed gemcitabine plus nab-paclitaxel in most cases, with some safety concerns leading to a maximum tolerated dose of palbociclib at 100 mg per cycle alongside nab-paclitaxel at 125 mg.
  • Although the treatment showed promise, the targeted 12-month survival rate of 65% was not achieved, indicating a need for further research.
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  • Tumor-associated macrophages (TAMs) are prevalent in pancreatic cancer, and their proliferation is influenced by colony stimulating factor-1 (CSF1) from cancer-associated fibroblasts.
  • High levels of p21 in TAMs are linked to more inflammatory and immunosuppressive behaviors, impacting both the macrophage phenotype and cancer progression.
  • The study suggests that regulating p21 in TAMs could enhance responses to cancer treatments, indicating a connection between macrophage behavior, immune suppression, and tumor therapy effectiveness.
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  • Ulixertinib is a new oral drug that inhibits ERK and has shown promise for patients with RAS-mutant cancers in earlier trials.
  • A phase Ib trial was conducted to assess the safety and effectiveness of combining ulixertinib with gemcitabine and nab-paclitaxel for patients with untreated metastatic pancreatic cancer, focusing on determining the recommended dose and evaluating various health outcomes.
  • The trial faced challenges, leading to a dose reduction of ulixertinib due to side effects, and although some patients showed partial responses, the high occurrence of adverse events resulted in the study being prematurely terminated.
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  • Targeting focal adhesion kinase (FAK) with the drug defactinib, combined with gemcitabine and pembrolizumab, shows promise in treating pancreatic ductal adenocarcinoma (PDAC) in a multi-center phase I study.* -
  • The study involved two phases: one to determine the optimal dosage and another to treat patients with either refractory or stable PDAC, where an 80% disease control rate was observed among those with refractory disease.* -
  • Preliminary results indicate the treatment combination is well-tolerated and shows potential efficacy, suggesting future studies may benefit from using stronger chemotherapy agents alongside it.*
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Purpose: Ablative radiation therapy for borderline resectable or locally advanced pancreatic ductal adenocarcinoma (BR/LA-PDAC) may limit concurrent chemotherapy dosing and usually is only safely deliverable to tumors distant from gastrointestinal organs. Magnetic resonance guided radiation therapy may safely permit radiation and chemotherapy dose escalation.

Methods And Materials: We conducted a single-arm phase I study to determine the maximum tolerated dose of ablative hypofractionated radiation with full-dose gemcitabine/nab-paclitaxel in patients with BR/LA-PDAC.

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Background & Aims: Checkpoint immunotherapy is largely ineffective in pancreatic ductal adenocarcinoma (PDAC). The innate immune nuclear factor (NF)-κB pathway promotes PDAC cell survival and stromal fibrosis, and is driven by Interleukin-1 Receptor Associated Kinase-4 (IRAK4), but its impact on tumor immunity has not been directly investigated.

Methods: We interrogated The Cancer Genome Atlas data to identify the correlation between NF-κB and T cell signature, and a PDAC tissue microarray (TMA) to correlate IRAK4 activity with CD8 T cell abundance.

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Gallbladder cancer (GBC) is a biological, anatomical, and clinically distinct subset of biliary tract cancers (BTC), which also include extra- and intra-hepatic cholangiocarcinoma. The advent of next-generation sequencing (NGS) clearly shows that GBC is genetically different from cholangiocarcinoma. Although GBC is a relatively rare cancer, it is highly aggressive and carries a grave prognosis.

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Combination chemotherapies remain the cornerstone treatment for pancreatic ductal adenocarcinoma (PDAC), but de novo and acquired resistance is common. In this study, we aimed to identify and characterize resistance mechanisms to a FIRINOX chemotherapy regimen (a combination of 5-fluorouracil, irinotecan, and oxaliplatin) because it is the most aggressive regimen currently used clinically for patients with PDAC. Using an unbiased reverse-phase protein array, we detected phospho-activation of heat shock protein 27 (Hsp27) as the most up-regulated event after FIRINOX treatment in PDAC cells.

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Pancreatic ductal adenocarcinoma (PDAC) remains highly refractory to treatment. While the oncogene is present in almost all PDAC cases and accounts for many of the malignant feats of PDAC, targeting KRAS or its canonical, direct effector cascades remains unsuccessful in patients. The recalcitrant nature of PDAC is also heavily influenced by its highly fibro-inflammatory tumor microenvironment (TME), which comprises an acellular extracellular matrix and various types of non-neoplastic cells including fibroblasts, immune cells, and adipocytes, underscoring the critical need to delineate the bidirectional signaling interplay between PDAC cells and the TME in order to develop novel therapeutic strategies.

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Pancreatic ductal adenocarcinoma (PDAC) patients have a dismal prognosis due in large part to chemotherapy resistance. However, a small subset containing defects in the DNA damage response (DDR) pathways are chemotherapy-sensitive. Identifying intrinsic and therapeutically inducible DDR defects can improve precision and efficacy of chemotherapies for PDAC.

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Development of candidate cancer treatments is a resource-intensive process, with the research community continuing to investigate options beyond static genomic characterization. Toward this goal, we have established the genomic landscapes of 536 patient-derived xenograft (PDX) models across 25 cancer types, together with mutation, copy number, fusion, transcriptomic profiles, and NCI-MATCH arms. Compared with human tumors, PDXs typically have higher purity and fit to investigate dynamic driver events and molecular properties via multiple time points from same case PDXs.

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