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Pancreatic ductal adenocarcinoma (PDAC) has a dismal prognosis with a 5-year overall survival of 11%. The disease is usually diagnosed at advanced stages, and systemic chemotherapy is the standard-of-care treatment for the majority of patients with PDAC. Although novel treatment options, such as targeted therapy and immunotherapy, have achieved substantial progress leading to practice-changing results, with FDA approvals for several solid tumors so far, the progress achieved for PDAC is relatively limited. Recent studies uncovered potential therapeutic targets for patients with PDAC, and potential therapeutic opportunities are currently being further examined. Herein, we review recent advances in systemic therapy regimens, including cytotoxic agents, targeted therapies, immunotherapy, and novel therapeutic options for managing patients with PDAC. We also elaborate on molecular profiling to guide treatment and existing therapeutic opportunities that may further advance the clinical care of patients with this devastating disease.

Despite recent advances, biliary tract cancer (BTC) is traditionally known as being hard to treat with a poor prognosis. Recent state-of-the-art genomic technologies such as next-generation sequencing (NGS) revolutionized cancer management and shed light on the genomic landscape of BTCs. There are ongoing clinical trials to assess the efficacy of HER2-blocking antibodies or drug conjugates in BTCs with HER2 amplifications. However, HER2 amplifications may not be the sole eligibility factor for these clinical trials. In this review, we aimed to comprehensively examine the role of somatic HER2 alterations and amplifications in patient stratification and provide an overview of the current state of ongoing clinical trials.

Sarcoidosis is an idiopathic inflammatory disorder that is commonly treated with glucocorticoids and there are no approved steroid-sparing medications. There is emerging evidence that Janus kinase (JAK) inhibitors, which inhibit JAK-dependent cytokine activity, may hold promise in sarcoidosis. In this open-label trial, 10 patients with recalcitrant sarcoidosis with cutaneous involvement were treated with tofacitinib 5 mg twice daily. There was no washout period and patients were permitted to continue, taper, or discontinue other treatments. The primary outcome was the change in the Cutaneous Sarcoidosis Activity and Morphology Instrument (CSAMI) activity score after 6 months. Change in internal organ disease activity was also assessed using total lesion glycolysis (TLG) determined by full-body positron emission tomography. A mean reduction in the CSAMI activity score of 82.7% was observed, with 6 patients showing a complete response. Internal organ response data was available in 8 patients; a decrease in TLG of ≥50% was noted in 5 patients, with complete or near complete resolution in 3 (>98% reduction in TLG). Patients were generally able to significantly taper or discontinue their baseline immunosuppressive regimen, which included prednisone in 5 patients. Single cell RNA-sequencing, bulk RNA-sequencing, and high-throughput proteomic analyses were performed on skin and blood as a function of treatment in order to delineate changes in immunologic signals with therapy. We identified CD4+ T cell derived IFN-γ as a central cytokine driver of sarcoidosis and inhibition of its activity was achieved with tofacitinib and correlated closely with clinical improvement. Tofacitinib appears to have impressive activity in treatment of sarcoidosis and likely acts by inhibiting IFN-γ, larger, controlled studies are warranted.

Summary Immunotherapy has revolutionized cancer treatment, yet most patients do not respond. Here, we investigated mechanisms of response by profiling the proteome of clinical samples from advanced stage melanoma patients undergoing either tumor infiltrating lymphocyte (TIL)-based or anti- programmed death 1 (PD1) immunotherapy. Using high-resolution mass spectrometry, we quantified over 10,300 proteins in total and ∼4,500 proteins across most samples in each dataset. Statistical analyses revealed higher oxidative phosphorylation and lipid metabolism in responders than in non-responders in both treatments. To elucidate the effects of the metabolic state on the immune response, we examined melanoma cells upon metabolic perturbations or CRISPR-Cas9 knockouts. These experiments indicated lipid metabolism as a regulatory mechanism that increases melanoma immunogenicity by elevating antigen presentation, thereby increasing sensitivity to T cell mediated killing both in vitro and in vivo. Altogether, our proteomic analyses revealed association between the melanoma metabolic state and the response to immunotherapy, which can be the basis for future improvement of therapeutic response.

Pancreaticductal adenocarcinoma (PDAC) is a cancer of the exocrine pancreas with an aggressive prognosis (a 5-year survival rate of 6 months), resulting in more than 250,000 deaths per year. PDAC is the fourth most common cause of cancer-related mortality worldwide. PDAC is more resistant to chemotherapy than other types of cancer due to the dense fibrosis around it. Moreover, only 15% of patients who have PDAC tumors can have surgical resection. Consequently, the success of chemotherapy and surgery in PDAC treatments is limited, motivating researchers to turn to immunotherapy modalities. The dense fibrotic nature of the PDAC microenvironment makes it worthwhile to research the cancer-associated fibroblasts (CAF). The CAF cells play a role in the formation of fibrotic barriers, the altering of the anti-tumor immune response, and supporting to carcinogenesis. Many immune system elements, such as macrophages and cytotoxic T cells, play a role in the formation of the anti-tumor immune response. Macrophages play a particularly crucial role in that anti-tumor immune response but in two opposing manners, activating classically or in alternative ways. Macrophages that activate in alternative manners, the tumor associated macrophages (TAMs), have become a focus in cancer research in recent years due to their role in suppressing the anti-tumor response, in supporting angiogenesis and metastasis. However, there is no consensus on how the TAM cells are polarized from monocytes. This study aims to determine whether or not CAF cells play a role in the polarization of TAMs through CXCL12/ CXCR4 axis, and how this role affects survival and tumor volume in PDAC patients. If we explore that CAFs play a role in macrophage polarization viaCXCL12 / CXCR4 axis in this study, we may suppress this pathway and gain clinical benefit from this inhibition in PDAC patients.