The biological underpinnings of therapeutic resistance in pancreatic cancer.

Pancreatic ductal adenocarcinoma (PDAC) is a leading cause of cancer-related mortality in the United States and has only recently achieved a 5-yr survival rate of 10%. This dismal prognosis reflects the remarkable capacity of PDAC to effectively adapt to and resist therapeutic intervention. In this review, we discuss recent advances in our understanding of the biological underpinnings of PDAC and their implications as targetable vulnerabilities in this highly lethal disease.

Targeting loss of heterozygosity for cancer-specific immunotherapy.

Developing therapeutic agents with potent antitumor activity that spare normal tissues remains a significant challenge. Clonal loss of heterozygosity (LOH) is a widespread and irreversible genetic alteration that is exquisitely specific to cancer cells. We hypothesized that LOH events can be therapeutically targeted by "inverting" the loss of an allele in cancer cells into an activating signal. Here we describe a proof-of-concept approach utilizing engineered T cells approximating NOT-gate Boolean logic to target counterexpressed antigens resulting from LOH events in cancer. The NOT gate comprises a chimeric antigen receptor (CAR) targeting the allele of human leukocyte antigen (HLA) that is retained in the cancer cells and an inhibitory CAR (iCAR) targeting the HLA allele that is lost in the cancer cells. We demonstrate that engineered T cells incorporating such NOT-gate logic can be activated in a genetically predictable manner in vitro and in mice to kill relevant cancer cells. This therapeutic approach, termed NASCAR (Neoplasm-targeting Allele-Sensing CAR), could, in theory, be extended to LOH of other polymorphic genes that result in altered cell surface antigens in cancers.

Vascular Impact of Cancer Therapies: The Case of BTK (Bruton Tyrosine Kinase) Inhibitors.

Novel targeted cancer therapies have revolutionized oncology therapies, but these treatments can have cardiovascular complications, which include heterogeneous cardiac, metabolic, and vascular sequelae. Vascular side effects have emerged as important considerations in both cancer patients undergoing active treatment and cancer survivors. Here, we provide an overview of vascular effects of cancer therapies, focusing on small-molecule kinase inhibitors and specifically inhibitors of BTK (Bruton tyrosine kinase), which have revolutionized treatment and prognosis for B-cell malignancies. Cardiovascular side effects of BTK inhibitors include atrial fibrillation, increased risk of bleeding, and hypertension, with the former 2 especially providing a treatment challenge for the clinician. Cardiovascular complications of small-molecule kinase inhibitors can occur through either on-target (targeting intended target kinase) or off-target kinase inhibition. We will review these concepts and focus on the case of BTK inhibitors, highlight the emerging data suggesting an off-target effect that may provide insights into development of arrhythmias, specifically atrial fibrillation. We believe that cardiac and vascular sequelae of novel targeted cancer therapies can provide insights into human cardiovascular biology.

Heart Failure With Targeted Cancer Therapies: Mechanisms and Cardioprotection.

Oncology has seen growing use of newly developed targeted therapies. Although this has resulted in dramatic improvements in progression-free and overall survival, challenges in the management of toxicities related to longer-term treatment of these therapies have also become evident. Although a targeted approach often exploits the differences between cancer cells and noncancer cells, overlap in signaling pathways necessary for the maintenance of function and survival in multiple cell types has resulted in systemic toxicities. In particular, cardiovascular toxicities are of important concern. In this review, we highlight several targeted therapies commonly used across a variety of cancer types, including HER2 (human epidermal growth factor receptor 2)+ targeted therapies, tyrosine kinase inhibitors, immune checkpoint inhibitors, proteasome inhibitors, androgen deprivation therapies, and MEK (mitogen-activated protein kinase kinase)/BRAF (v-raf murine sarcoma viral oncogene homolog B) inhibitors. We present the oncological indications, heart failure incidence, hypothesized mechanisms of cardiotoxicity, and potential mechanistic rationale for specific cardioprotective strategies.

Update on Small Molecule Targeted Therapies for Acute Myeloid Leukemia.

OPINION STATEMENT: The search for effective therapies for the highly heterogenous disease acute myeloid leukemia (AML) has remained elusive. While cytotoxic therapies can induce complete remission and even, at times, long-term survival, this approach is associated with significant toxic effects to visceral organs and worsening of immune dysfunction and marrow suppression leading to death. Sophisticated molecular studies have revealed defects within the AML cell that can be exploited by utilizing small molecule agents to target these defects, often dubbed "target therapy." Several medications have already established new standards of care for many patients with AML, including FDA-approved agents that inhibitor IDH1, IDH2, FLT3, and BCL-2. Emerging small molecules hold additional to add to the armamentarium of AML treatment options including MCL-1 inhibitors, TP53 inhibitors, menin inhibitors, and E-selectin antagonists. Moreover, the increasing options also mean that future combinations of these agents need to be explored, including with cytotoxic drugs and other newer emerging strategies such as immunotherapies for AML. Recent investigations continue to show that overcoming many of the challenges of treating AML finally is on the horizon.

[Strategies for liver injury caused by hepatocellular carcinoma targeted therapy].

Primary hepatocellular carcinoma has a high degree of malignancy, insidious onset, and rapid progression that seriously threatens human life and health. With the continuous deepening of the study of the molecular characteristics of tumors, molecular targeted drugs have become an important treatment method for patients with advanced liver cancer. Liver injury is one of the common adverse reactions of targeted drugs, which needs to be paid attention to. This paper mainly briefly expounds on the occurrence condition, mechanism, risk factors, diagnosis, and treatment of liver injury caused by hepatocellular carcinoma targeted therapy in order to provide a reference for the safe clinical application of targeted drugs.

Pharmacogenomics meets precision cardio-oncology: is there synergistic potential?

An individual's inherited genetic makeup and acquired genomic variants may account for a significant portion of observable variability in therapy efficacy and toxicity. Pharmacogenomics (PGx) is the concept that treatments can be modified to account for these differences to increase chances of therapeutic efficacy while minimizing risk of adverse effects. This is particularly applicable to oncology in which treatment may be multimodal. Each tumor type has a unique genomic signature that lends to inclusion of targeted therapy but may be associated with cumulative toxicity, such as cardiotoxicity, and can impact quality of life. A greater understanding of therapeutic agents impacted by PGx and subsequent implementation has the potential to improve outcomes and reduce risk of drug-induced adverse effects.

Pharmacogenomics for immunotherapy and immune-related cardiotoxicity.

Immune checkpoint blockade (ICB) has become a standard of care in a subset of solid tumors. Although cancer survivorship has extended, rates of durable response of ICB remain poor; furthermore, cardiac adverse effects are emerging, which impact several mechanical aspects of the heart. Cardio-oncology programs implement a clinical assessment to curtail cardiovascular disease progression but are limited to the current clinical parameters used in cardiology. Pharmacogenomics provides the potential to unveil heritable and somatic genetic variations for guiding precision immunotherapy treatment to reduce the risk of immune-related cardiotoxicity. A better understanding of pharmacogenomics will optimize the current treatment selection and dosing of immunotherapy. Here, we summarize the recent pharmacogenomics studies in immunotherapy responsiveness and its related cardiotoxicity and highlight how patient genetics and epigenetics can facilitate researchers and clinicians in designing new approaches for precision immunotherapy. We highlight and discuss how single-cell technologies, human-induced pluripotent stem cells and systems pharmacogenomics accelerate future studies of precision cardio-oncology.

Updates on targeted therapies for acute myeloid leukaemia.

In the past few years research in the underlying pathogenic mechanisms of acute myeloid leukaemia (AML) has led to remarkable advances in our understanding of the disease. Cytogenetic and molecular aberrations are the most important factors in determining response to chemotherapy as well as long-term outcome, but beyond prognostication are potential therapeutic targets. Our increased understanding of the pathogenesis of AML facilitated by next-generation sequencing has spurred the development of new compounds in the treatment of AML, particularly the creation of small molecules that target the disease on a molecular level. Many of the hopeful predictions outlined in our AML review of 2018 are now therapeutic realities: gemtuzumab ozogamicin, venetoclax, FLT3 inhibitors (midostaurin, gilteritinib), IDH inhibitors (ivosidenib, enasidenib), CPX-351, glasdegib, oral decitabine, and oral azacitidine. Others may soon be (quizartinib, APR246 magrolimab, menin inhibitors). The wealth of positive data allows reconsideration of what might soon be new standards of care in younger and older patients with AML. In this review we give an overview of recently approved therapies in AML and address present and future research directions.

Cardiotoxicity of Cancer Treatments: Focus on Anthracycline Cardiomyopathy.

Significant progress has been made in developing new treatments and refining the use of preexisting ones against cancer. Their successful use and the longer survival of cancer patients have been associated with reports of new cardiotoxicities and the better characterization of the previously known cardiac complications. Immunotherapies with monoclonal antibodies against specific cancer-promoting genes, chimeric antigen receptor T cells, and immune checkpoint inhibitors have been developed to fight cancer cells, but they can also show off-target effects on the heart. Some of these cardiotoxicities are thought to be due to nonspecific immune activation and inflammatory damage. Unlike immunotherapy-associated cardiotoxicities which are relatively new entities, there is extensive literature on anthracycline-induced cardiomyopathy. Here, we provide a brief overview of the cardiotoxicities of immunotherapies for the purpose of distinguishing them from anthracycline cardiomyopathy. This is especially relevant as the expansion of oncological treatments presents greater diagnostic challenges in determining the cause of cardiac dysfunction in cancer survivors with a history of multiple cancer treatments including anthracyclines and immunotherapies administered concurrently or serially over time. We then provide a focused review of the mechanisms proposed to underlie the development of anthracycline cardiomyopathy based on experimental data mostly in mouse models. Insights into its pathogenesis may stimulate the development of new strategies to identify patients who are susceptible to anthracycline cardiomyopathy while permitting low cardiac risk patients to receive optimal treatment for their cancer.

Arterial Thrombotic Complications of Tyrosine Kinase Inhibitors.

Abnormal expression or function of several classes of kinases contribute to the development of many types of solid and hematologic malignancies. TKs (tyrosine kinases) in particular play a role in tumor growth, metastasis, neovascularization, suppression of immune surveillance, and drug resistance. TKIs (tyrosine kinase inhibitors) targeted to TKs such as BCR-ABL1, VEGF receptors, PDGF receptors, have transformed therapy of certain forms of cancer by providing excellent efficacy with relatively low adverse event rates. Yet some of these agents have been associated with high rates of vascular events, presumably from prothrombotic complications that result in myocardial infarction, stroke, and critical limb ischemia. This review describes the scope of the problem evidenced by clinical experience with some of the most commonly used TKIs, with a focus on TKIs targeted to the BCR-ABL1 (breakpoint cluster region-Abelson 1) translocation. We also discuss the potential mechanisms responsible for arterial thrombotic complications that could lead to mitigation strategies or unique TK targeting strategies to reduce adverse event rates without compromising efficacy.

Cancer Therapy-Associated Thrombosis.

[Figure: see text].

Chronic Lymphocytic Leukemia: Chemotherapy Free and Other Novel Therapies Including CAR T.

OPINION STATEMENT: Chronic lymphocytic leukemia (CLL) is the most common leukemia in adults. Most individuals diagnosed with CLL will not need treatment immediately but over time the clonal B cells infiltrate the bone marrow, lymph nodes, liver, and spleen, causing anemia, thrombocytopenia, systemic symptoms, and increased risk for infections. When clonal B cells begin adversely affecting other organs, treatment is warranted. Therapy for CLL has undergone a paradigm shift away from chemotherapy-based regimens to targeted therapy with small-molecule inhibitors. B-cell receptor (BCR) signaling plays a key role in CLL. BCR signaling occurs via many factors including Bruton's tyrosine kinase (BTK), phosphatidylinositol 3-kinase (PI3K), phosphatidylinositol-4,5-bisphosphonate phosphodiesterase gamma-2 (PLCγ2), and CD19. CLL cells also express high levels of B-cell lymphoma or leukemia 2 (BCL2). Drugs that interfere with these pathways, such as ibrutinib, venetoclax, and idelalisib, have improved clinical outcomes. For any CLL patient that meets criteria for treatment, after evaluating for prognostic cytogenetic abnormalities, oral BTK inhibitors or venetoclax in combination with anti-CD20 therapy are considered first-line therapy. It is important to note that these novel therapies are particularly preferred for patients with TP53 mutations or deletion of the small arm of chromosome 17 (del(17p)), as those patients usually are chemotherapy refractory or display short remissions to chemotherapy. Nevertheless, patients without high-risk features such as TP53 abnormalities also benefit from novel agents. Following relapse, depending on the primary oral agent used, BTK inhibitors, venetoclax in combination with anti-CD20 antibodies, or PI3K inhibitors are preferred.

Genetic Therapy and Molecular Targeted Therapy in Oncology: Safety, Pharmacovigilance, and Perspectives for Research and Clinical Practice.

The impressive advances in the knowledge of biomarkers and molecular targets has enabled significant progress in drug therapy for crucial diseases such as cancer. Specific areas of pharmacology have contributed to these therapeutic outcomes-mainly targeted therapy, immunomodulatory therapy, and gene therapy. This review focuses on the pharmacological profiles of these therapeutic classes and intends, on the one hand, to provide a systematic definition and, on the other, to highlight some aspects related to pharmacovigilance, namely the monitoring of safety and the identification of potential toxicities and adverse drug reactions. Although clinicians often consider pharmacovigilance a non-priority area, it highlights the risk/benefit ratio, an essential factor, especially for these advanced therapies, which represent the most innovative and promising horizon in oncology.

Cellular dormancy in minimal residual disease following targeted therapy.

BACKGROUND: Breast cancer mortality is principally due to tumor recurrence, which can occur following extended periods of clinical remission that may last decades. While clinical latency has been postulated to reflect the ability of residual tumor cells to persist in a dormant state, this hypothesis remains unproven since little is known about the biology of these cells. Consequently, defining the properties of residual tumor cells is an essential goal with important clinical implications for preventing recurrence and improving cancer outcomes. METHODS: To identify conserved features of residual tumor cells, we modeled minimal residual disease using inducible transgenic mouse models for HER2/neu and Wnt1-driven tumorigenesis that recapitulate cardinal features of human breast cancer progression, as well as human breast cancer cell xenografts subjected to targeted therapy. Fluorescence-activated cell sorting was used to isolate tumor cells from primary tumors, residual lesions following oncogene blockade, and recurrent tumors to analyze gene expression signatures and evaluate tumor-initiating cell properties. RESULTS: We demonstrate that residual tumor cells surviving oncogenic pathway inhibition at both local and distant sites exist in a state of cellular dormancy, despite adequate vascularization and the absence of adaptive immunity, and retain the ability to re-enter the cell cycle and give rise to recurrent tumors after extended latency periods. Compared to primary or recurrent tumor cells, dormant residual tumor cells possess unique features that are conserved across mouse models for human breast cancer driven by different oncogenes, and express a gene signature that is strongly associated with recurrence-free survival in breast cancer patients and similar to that of tumor cells in which dormancy is induced by the microenvironment. Although residual tumor cells in both the HER2/neu and Wnt1 models are enriched for phenotypic features associated with tumor-initiating cells, limiting dilution experiments revealed that residual tumor cells are not enriched for cells capable of giving rise to primary tumors, but are enriched for cells capable of giving rise to recurrent tumors, suggesting that tumor-initiating populations underlying primary tumorigenesis may be distinct from those that give rise to recurrence following therapy. CONCLUSIONS: Residual cancer cells surviving targeted therapy reside in a well-vascularized, desmoplastic microenvironment at both local and distant sites. These cells exist in a state of cellular dormancy that bears little resemblance to primary or recurrent tumor cells, but shares similarities with cells in which dormancy is induced by microenvironmental cues. Our observations suggest that dormancy may be a conserved response to targeted therapy independent of the oncogenic pathway inhibited or properties of the primary tumor, that the mechanisms underlying dormancy at local and distant sites may be related, and that the dormant state represents a potential therapeutic target for preventing cancer recurrence.

Infections in patients with lymphoproliferative diseases treated with targeted agents: SEIFEM multicentric retrospective study.

We describe the opportunistic infections occurring in 362 patients with lymphoproliferative disorders treated with ibrutinib and idelalisib in clinical practice. Overall, 108 of 362 patients (29·8%) developed infections, for a total of 152 events. Clinically defined infections (CDI) were 49·3% (75/152) and microbiologically defined infections (MDI) were 50·7% (77/152). Among 250 patients treated with ibrutinib, 28·8% (72/250) experienced one or more infections, for a total of 104 episodes. MDI were 49% (51/104). Bacterial infections were 66·7% (34/51), viral 19·6% (10/51) and invasive fungal diseases (IFD) 13·7% (7/51). Among the 112 patients treated with idelalisib, 32·1% (36/112) experienced one or more infections, for a total of 48 episodes. MDI were 54·2% (26/48). Bacterial infections were 34·6% (9/26), viral 61·5% (16/26) and IFD 3·8% (1/26). With ibrutinib, the rate of bacterial infections was significantly higher compared to idelalisib (66·7% vs. 34·6%; P = 0·007), while viral infections were most frequent in idelalisib (61·5% vs. 19·6%; P < 0·001). Although a higher rate of IFD was observed in patients treated with ibrutinib, the difference was not statistically significant (13·7% vs. 3·8% respectively; P = 0·18). Bacteria are the most frequent infections with ibrutinib, while viruses are most frequently involved with idelalisib.

Therapeutic Landscape for NAFLD in 2020.

Lifestyle modifications focused on healthy eating and regular exercise are the primary recommendations for patients with nonalcoholic steatohepatitis (NASH). However, for multiple societal, psychological, physical, genetic, and epigenetic reasons, the ability of people to adopt and sustain such changes is challenging and typically not successful. To end the epidemic of NASH and prevent its complications, including cirrhosis and hepatocellular carcinoma, pharmacological interventions are now being evaluated in clinical trials. Treatments include drugs targeting energy intake, energy disposal, lipotoxic liver injury, and the resulting inflammation and fibrogenesis that lead to cirrhosis. It is likely that patients develop the phenotype of NASH by multiple mechanisms, and thus the optimal treatments of NASH will likely evolve to personalized therapy once we understand the mechanistic underpinnings of NASH in each patient. Reviewed here is the treatment landscape in this rapidly evolving field with an emphasis on drugs in Phase 2 and Phase 3 trials.

Normalization of electroretinogram and symptom resolution of melanoma-associated retinopathy with negative autoantibodies after treatment with programmed death-1 (PD-1) inhibitors for metastatic melanoma.

Melanoma-associated retinopathy (MAR) is a paraneoplastic syndrome that involves the production of autoantibodies which can cross-react with retinal epitopes leading to visual symptoms. Autoantibodies can target intracellular proteins, and only a few are directed against membrane proteins. This discrepancy in autoantibody-protein target can translate into different immune responses (T-cell mediated vs B-cell mediated). Historically, treatment of MAR has focused on surgical reduction or immunosuppressive medication, mainly glucocorticoids. However, tumor resection is not relevant in metastatic melanoma in which MAR is mostly encountered. Moreover, the use of glucocorticoids can reduce the efficacy of immunotherapy. We report the first case to our knowledge with subjective resolution of visual symptoms and objective evidence of normalization of electroretinogram of MAR with undetectable autoantibodies after administration of programmed death-1 (PD-1) inhibitor (pembrolizumab) without the use of surgical reduction or systemic immunosuppression. This case highlights the potential improvement and resolution of negative autoantibody MAR with the use of PD-1 inhibitors and emphasizes the importance of multidisciplinary approach and team discussion to avoid interventions that can decrease immunotherapy-mediated anti-tumor effect.

Immune-related adverse events: promising predictors for efficacy of immune checkpoint inhibitors.

PURPOSE: This study was designed to investigate the correlation between immune-related adverse events (irAEs) of immune checkpoint inhibitors (ICIs) and corresponding efficacy, and to explore the potential of predicting the efficacy of ICIs via irAEs. METHODS: Electronic databases including PubMed, Embase, Cochrane Library, CNKI and Wanfang were applied to search for relevant studies. The primary endpoint was overall survival (OS) or progression-free survival (PFS), and the secondary endpoint was objective response rate (ORR). Stratification analyses were conducted according to the type of irAEs and ICIs, region of studies and primary tumors. Furthermore, statistical analyses were realized by means of RevMan 5.3 software. RESULTS: Altogether, 40 studies with 8,641 participants were enrolled, among which the incidence of irAEs ranged from 15.34 to 85.23% and the major sites reached out to skin, endocrine organ, gastrointestinal tract, liver and lung. The ORR, OS and PFS in irAE group were significantly higher than those in non-irAE group as per pooled analyses and stratification analyses. Importantly, patients with irAEs in skin, endocrine organ or gastrointestinal tract rather than in liver and lung were found to obtain survival benefits (p < 0.05). CONCLUSION: IrAEs, especially in skin, endocrine organ or gastrointestinal tract, triggered by ICIs indicate significant survival benefits.

How targeted therapy disrupts the treatment paradigm for acquired TTP: the risks, benefits, and unknowns.

Insights into immune-mediated thrombotic thrombocytopenic purpura (iTTP) pathophysiology have led to novel targeted therapies. Immunomodulatory strategies target anti-ADAMTS13 antibodies: rituximab is effective in inducing responses in refractory/relapsed TTP and increasing relapse-free survival; caplacizumab targets the von Willebrand factor-platelet interaction to hasten platelet count recovery and reduce mortality and TTP-related ischemic events. Bortezomib and recombinant ADAMTS13 are under investigation. This review examines how targeted therapies are disrupting current treatment paradigms to improve outcomes of iTTP.