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Simple Summary: Gallbladder cancer is distinct type of biliart tract cancer that is rare, aggressive and with limited treatment options aside from surgical resection. As of now in year 2022, systemic chemotherapy remains as the mainstay treatment option for patients with advanced staged gallbladder cancer. Despite decades of scientific research, new treatment options have been struggling to succeed. Furthermore, almost all clinical studies on gallbladder cancer have included other tyes of biliary tract cancers, raising the need to specifically inspect the outcomes of these clinical trial regimens on gallbladder cancer. In this article, we summarized all seminal literature and the most recent advances in scientific discoveries and clinical trials on gallbladder cancer. We provide a succinct update on current understanding, treatment landscape and therapeutic challenges in gallbladder cancer, as well as future prospects in the management of this disease. 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. To date, complete surgical resection remains the only path for cure but is limited to patients with early-stage disease. The majority of the patients are diagnosed at an advanced, inoperable stage when systemic treatment is administered as an attempt to enable surgery or for palliation. Gemcitabine and platinum-based chemotherapies have been the main treatment modality for unresectable, locally advanced, and metastatic gallbladder cancer. However, over the past decade, the treatment paradigm has evolved. These include the introduction of newer chemotherapeutic strategies after progression on frontline chemotherapy, incorporation of targeted therapeutics towards driver mutations of genes including HER2, FGFR, BRAF, as well as approaches to unleash host anti-tumor immunity using immune checkpoint inhibitors. Notably, due to the rarity of BTC in general, most clinical trials included both GBC and cholangiocarcinomas. Here, we provide a review on the pathogenesis of GBC, past and current systemic treatment options focusing specifically on GBC, clinical trials tailored towards its genetic mutations, and emerging treatment strategies based on promising recent clinical studies. [ABSTRACT FROM AUTHOR]

Simple Summary: Oncogenic KRAS signaling drives several effector cascades that contribute not only to the malignant behavior of pancreatic cancer cells but also formation of the fibro-inflammatory microenvironment. The non-neoplastic cells in the tumor microenvironment interact with tumor cells, creating a complex onco-inflammatory signaling network that enhances the resilience of cancer cells and potentially explaining why targeting KRAS effectors is clinically ineffective. We provide a focused review of this onco-inflammatory network and discuss novel therapeutic opportunities that can be developed. Pancreatic ductal adenocarcinoma (PDAC) remains highly refractory to treatment. While the KRAS 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. The impact of tumor-cell KRAS signaling on various cell types in the TME has been well covered by several reviews. In this article, we critically reviewed evidence, including work from our group, on how the feedback inflammatory signals from the TME impact and synergize with oncogenic KRAS signaling in PDAC cells, ultimately augmenting their malignant behavior. We discussed past and ongoing clinical trials that target key inflammatory pathways in PDAC and highlight lessons to be learned from outcomes. Lastly, we provided our perspective on the future of developing therapeutic strategies for PDAC through understanding the breadth and complexity of KRAS and the inflammatory signaling network. [ABSTRACT FROM AUTHOR]

Simple Summary: Defining the mechanisms underlying the heterogeneous cancer cell response to DNA damage is important for our ability to tailor individualized strategies to improve chemotherapy efficacy. In this study, we focus on a central DNA repair regulator named VCP whose loss-of-function has been shown by prior studies to increase chemotherapy effects. However, since VCP participates in numerous cellular processes, its total expression level cannot differentiate between VCP-dependent vs. -independent tumors with specific regard to chemotherapy-induced DNA repair. Here, by examining cell lines and patient samples of pancreatic ductal adenocarcinoma (PDAC), we made two major observations. First, DNA damage-induced Ser784 phosphorylation is essential for DNA repair by VCP and drives chemo-resistance. Second, pSer784-VCP instead of total VCP protein predicts cellular reliance on VCP function during DNA repair and consequently chemo-sensitizing effects of VCP inhibition. Thus, pSer784-VCP may be a potential predictive biomarker and sensitizing target for cancer chemotherapy treatments. 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. DNA repair requires dynamic reorganization of chromatin-associated proteins, which is orchestrated by the AAA+ ATPase VCP. We recently discovered that the DDR function of VCP is selectively activated by Ser784 phosphorylation. In this paper, we show that pSer784-VCP but not total VCP levels in primary PDAC tumors negatively correlate with patient survival. In PDAC cell lines, different pSer784-VCP levels are induced by genotoxic chemotherapy agents and positively correlate with genome stability and cell survival. Causal effects of pSer784-VCP on DNA repair and cell survival were confirmed using VCP knockdown and functional rescue. Importantly, DNA damage-induced pSer784-VCP rather than total VCP levels in PDAC cell lines predict their chemotherapy response and chemo-sensitizing ability of selective VCP inhibitor NMS-873. Therefore, pSer784-VCP drives genotoxic chemotherapy resistance of PDAC, and can potentially be used as a predictive biomarker as well as a sensitizing target to enhance the chemotherapy response of PDAC. [ABSTRACT FROM AUTHOR]

Simple Summary: Liver metastasis is a major therapeutic challenge and common cause of death for patients with colorectal cancer. While systemic treatment especially chemotherapy remains the mainstay of treatment, selected patients with liver-only metastasis may further benefit from liver-directed therapies. Direct infusion of chemotherapy into the liver metastases via an implantable hepatic arterial infusion pump (HAIP) is potentially an effective way to improve treatment response and survival in selected patients. Here, we reviewed the literature utilizing HAIP as a liver-directed modality alone and in combination with systemic chemotherapy. We discussed two cases who were successfully treated with this combinatorial approach and achieved remission or prolongation of disease control. We discussed the limitations, toxicities of combined systemic and HAIP modalities. Lastly, we provided insights on the use of HAIP in the modern era of systemic treatment for colorectal cancer patients with liver metastasis. Colorectal cancer (CRC) is the third most prevalent malignancy and the second most common cause of death in the US. Liver is the most common site of colorectal metastases. About 13% of patients with colorectal cancer have liver metastasis on initial presentation and 50% develop them during the disease course. Although systemic chemotherapy and immunotherapy are the mainstay treatment for patients with metastatic disease, for selected patients with predominant liver metastasis, liver-directed approaches may provide prolonged disease control when combined with systemic treatments. Hepatic artery infusion pump (HAIP) chemotherapy is an approach which allows direct infusion of chemotherapeutic into the liver and is especially useful in the setting of multifocal liver metastases. When combined with systemic chemotherapy, HAIP improves the response rate, provides more durable disease control, and in some patients leads to successful resection. To ensure safety, use of HAIP requires multidisciplinary collaboration between interventional radiologists, medical oncologists, hepatobiliary surgeons and treatment nurses. Here, we review the benefits and potential risks with this approach and provide our single institution experience on two CRC patients successfully treated with HAIP in combination with systemic chemotherapy. We provide our recommendations in adopting this technique in the current era for patient with colorectal liver metastases. [ABSTRACT FROM AUTHOR]

Simple Summary: Chronic inflammation is a major mechanism that underlies the aggressive nature and treatment resistance of pancreatic cancer. In many ways, the molecular mechanisms that drive chronic inflammation in pancreatic cancer are very similar to our body's normal innate immune response to injury or invading microorganisms. Therefore, during cancer development, pancreatic cancer cells hijack the innate immune pathway to foster a chronically inflamed tumor environment that helps shield them from immune attack and therapeutics. While blocking the innate immune pathway is theoretically reasonable, untoward side effects must also be addressed. In this review, we comprehensively summarize the literature that describe the role of innate immune signaling in pancreatic cancer, emphasizing the specific role of this pathway in different cell types. We review the interaction of the innate immune pathway and cancer-driving signaling in pancreatic cancer and provide an updated overview of novel therapeutic opportunities against this mechanism. Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers with no effective treatment option. A predominant hallmark of PDAC is the intense fibro-inflammatory stroma which not only physically collapses vasculature but also functionally suppresses anti-tumor immunity. Constitutive and induced activation of the NF-κB transcription factors is a major mechanism that drives inflammation in PDAC. While targeting this pathway is widely supported as a promising therapeutic strategy, clinical success is elusive due to a lack of safe and effective anti-NF-κB pathway therapeutics. Furthermore, the cell type-specific contribution of this pathway, specifically in neoplastic cells, stromal fibroblasts, and immune cells, has not been critically appraised. In this article, we highlighted seminal and recent literature on molecular mechanisms that drive NF-κB activity in each of these major cell types in PDAC, focusing specifically on the innate immune Toll-like/IL-1 receptor pathway. We reviewed recent evidence on the signaling interplay between the NF-κB and oncogenic KRAS signaling pathways in PDAC cells and their collective contribution to cancer inflammation. Lastly, we reviewed clinical trials on agents that target the NF-κB pathway and novel therapeutic strategies that have been proposed in preclinical studies. [ABSTRACT FROM AUTHOR]