Showing papers in "Expert Opinion on Investigational Drugs in 2021"
TL;DR: Hepatocellular carcinoma (HCC) represents the sixth most commonly diagnosed malignancy worldwide, accounting for millions of deaths annually as mentioned in this paper. Despite immune checkpoint inhibitors (ICIs) reported im...
Abstract: Hepatocellular carcinoma (HCC) represents the sixth most commonly diagnosed malignancy worldwide, accounting for millions of deaths annually. Despite immune checkpoint inhibitors (ICIs) reported im...
80 citations
TL;DR: The anti-PD-L1 inhibitor durvalumab is currently under investigation in several clinical trials as monotherapy, or in combination with other pharmacological agents as mentioned in this paper, which may provide more effective, much needed treatment options.
Abstract: Introduction: The prognosis of patients with advanced biliary tract cancer (BTC) remains dismal, with a 5-year overall survival rate of less than 10%. Although immune checkpoint inhibitors (ICIs) have revolutionized the treatment landscape of several hematological and solid tumors, controversial results have been reported in BTC. In this setting, the anti-PD-L1 inhibitor durvalumab is currently under investigation in several clinical trials as monotherapy, or in combination with other pharmacological agents.Areas covered: We offer an overview of immunotherapies for BTC, discuss recently published or presented data on durvalumab pharmacology, safety, and efficacy in the treatment of BTC and consider future research directions for the agent in this setting.Expert opinion: The promising antitumor activity shown by durvalumab in early trials warrants further investigation because it may provide more effective, much needed treatment options. The results of clinical trials of this PD-L1 inhibitor, as a monotherapy or in combination, are eagerly awaited. Future efforts should focus on the identification and development of reliable biomarkers of response to durvalumab in BTC, clarifying the role of PD-L1 expression, microsatellite instability (MSI), mismatch repair (MMR), tumor mutational burden (TMB) and other emerging predictors.
71 citations
TL;DR: In this paper, the mainstay of medical treatment for advanced hepatocellular carcinoma (HCC) patients for more than a decade, novel agents and combination the sorafenib monotherapy were proposed.
Abstract: Introduction: While sorafenib monotherapy represented the mainstay of medical treatment for advanced hepatocellular carcinoma (HCC) patients for more than a decade, novel agents and combination the...
67 citations
TL;DR: This review provides an overview regarding the current scenario of FGFR2 targeted therapies in iCCA, especially focusing on the mechanism of action and clinical development of futibatinib (TAS-120), a highly selective irreversible pan-FGFR antagonist.
Abstract: Biliary tract cancers (BTCs) are poor prognosis malignancies usually classified in intrahepatic cholangiocarcinoma (iCCA), extrahepatic cholangiocarcinoma, gallbladder cancer, and ampulla of Vater ...
65 citations
TL;DR: In this article, the first-line treatment option for wet age-related macular degeneration (w-AMD) and diabetic macular edema (DME) was presented.
Abstract: Intravitreal antivascular endothelial growth factor (VEGF) drugs represent the first-line treatment option for wet age-related macular degeneration (w-AMD) and diabetic macular edema (DME); however...
56 citations
TL;DR: In this article, the authors discuss potential predictors of response to immunotherapy in breast cancer, including PD-L1 expression, tumor-infiltrating lymphocytes (TILs), tumor mutational burden (TMB), and several other biomarkers and suggest future directions of research in this setting.
Abstract: Introduction Immune checkpoint inhibitors (ICIs) have recently entered into the therapeutic scenario of metastatic breast cancer. However, only a proportion of patients benefit from ICIs and immune-based combinations, so the identification of reliable predictors of response remains an unmet need. Areas covered We discuss potential predictors of response to ICIs in breast cancer, including PD-L1 expression, tumor-infiltrating lymphocytes (TILs), tumor mutational burden (TMB), and several other biomarkers and suggest future directions of research in this setting. A literature search was conducted in October 2021 of Pubmed/Medline, Cochrane library and Scopus databases; in addition, abstract of international cancer meetings were reviewed. Expert opinion In terms of predictors of response to immunotherapy in TNBC patients, several biomarkers are being evaluated. Valuable data on predictive biomarkers have recently emerged, including host-related factors, immune-related cells, and protein and genetic markers. Data supporting immunotherapy in the metastatic triple-negative breast cancer setting are not concordant, but there have been some positive phase III trials including IMpassion130 and KEYNOTE-355. Phase II and III (neo)adjuvant trials are supportive of this therapeutic strategy. Further investigations are warranted in this challenging area.
54 citations
TL;DR: In this paper, the authors discuss the main evidence regarding the use of 90Y-TARE in HCC, the recent progress of immunotherapy in this tumor, and the preclinical rationale of combining VEGF blockade with the other two treatment strategies.
Abstract: INTRODUCTION The treatment algorithm of advanced hepatocellular carcinoma (HCC) has evolved since the introduction of immunotherapy. The IMbrave150 trial set atezolizumab-bevacizumab as a new standard-of-care first-line treatment for unresectable HCC patients. However, for patients with intermediate or advanced stage with portal vein thrombosis but without distant metastases, 90Yttrium transarterial radioembolization (90Y-TARE) is considered the treatment of choice. AREAS COVERED We discuss the main evidence regarding the use of 90Y-TARE in HCC, the recent progress of immunotherapy in this tumor, and the preclinical rationale of combining VEGF blockade with the other two treatment strategies. EXPERT OPINION HCC has an extremely heterogeneous tumor immune microenvironment. This may explain the inconsistent outcomes obtained with immune-checkpoint inhibitors. The identification of patients who could benefit most from immunotherapy is crucial; however, reliable markers of response are lacking. Radiation therapy and VEGF inhibition have an established synergism with immunotherapy, mainly linked to enhanced antigen presentation and reduced immunosuppressive immune infiltrate. Combining an immune-checkpoint inhibitor with VEGF blockade and 90Y-TARE might hence overcome primary resistances observed when each of these treatments is administerd alone.
39 citations
TL;DR: Duchenne muscular dystrophy (DMD) is an X-linked recessive disorder caused by mutations in the dystrophin gene as discussed by the authors, and most patients die from respiratory failure or cardiomyopathy.
Abstract: Duchenne muscular dystrophy (DMD) is an X-linked recessive disorder caused by mutations in the dystrophin (DMD) gene. Most patients die from respiratory failure or cardiomyopathy. There are signifi...
28 citations
TL;DR: A review of state-of-the-art immune-based combinations for metastatic triple negative breast cancer (mTNBC) can be found in this article, where the authors present a synopsis of current, state of the art immunebased combinations in this setting and reflect on future possibilities.
Abstract: Introduction Immune checkpoint inhibitor (ICI) monotherapy appears to be effective in a small cohort of patients with metastatic triple negative breast cancer (mTNBC). This supports the exploration of strategies for increasing the efficacy of immunotherapy. To enhance overall response and clinical outcomes, several immune-based combinations are being investigated. Areas covered The authors present a synopsis of current, state of art immune-based combinations in this setting and reflect on future possibilities. They shed light on recently presented and published clinical trials and ongoing studies. A literature search was conducted in October 2021; in addition, abstracts of international cancer meetings were reviewed. Expert opinion Clinical trials suggest that ICI monotherapy could be beneficial in a minority of mTNBC patients; conversely, several immune-based combinations have reported notable results in recently presented or published studies. Some of these combination strategies have been approved for mTNBC - as in the case of chemoimmunotherapy in PD-L1 positive patients. Numerous trials are investigating novel ICI-based combinations and their results are eagerly awaited.
27 citations
TL;DR: Uterine myomas and endometriosis are benign hormone dependent diseases affecting women of reproductive age as mentioned in this paper, and substantial efforts have been made to develop innovative medical options for treating the...
Abstract: Uterine myomas and endometriosis are benign hormone-dependent diseases affecting women of reproductive age. Substantial efforts have been made to develop innovative medical options for treating the...
26 citations
TL;DR: Generalized myasthenia gravis (gMG) is an autoimmune disorder in which pathogenic autoantibodies damage the neuromuscular junction, causing disabling or life-threatening muscle weakness as discussed by the authors.
Abstract: Generalized myasthenia gravis (gMG) is an autoimmune disorder in which pathogenic autoantibodies damage the neuromuscular junction, causing disabling or life-threatening muscle weakness. Most treat...
TL;DR: The fibroblast growth factor receptor (FGFR) pathway is essential in cell proliferation, differentiation, migration, and survival as discussed by the authors, and it is essential for cell proliferation and differentiation.
Abstract: The fibroblast growth factor receptor (FGFR) pathway is essential in cell proliferation, differentiation, migration, and survival. Cancers such as intrahepatic cholangiocarcinoma (IHCA) have demons...
TL;DR: In this paper, the authors proposed two concepts, namely precision oncology and precision precision cancer, for the treatment of cancer of the biliary tract (BTC) with limited treatment options and an overall dismal prognosis.
Abstract: Introduction: Cancers of the biliary tract (BTC) are aggressive malignancies with limited treatment options and an overall dismal prognosis. In recent years, two concepts, namely precision oncology...
TL;DR: This review illuminates those investigational drugs and cell therapies that are currently in early phase clinical trials for the treatment of DLBCL and suggests a focus on the optimal sequencing of the emergingDLBCL drugs is appropriate and necessary.
Abstract: Introduction: Diffuse large B cell lymphoma (DLBCL) is the most frequent lymphoma in adults. 30-40% DLBCL eventually relapse and 10% are primary refractory, posing an unmet clinical need, especially in patients not eligible for hematopoietic stem cell transplant. Knowledge of DLBCL molecular pathogenesis has identified druggable molecular pathways. Surface antigens can be targeted by novel antibodies and innovative cell therapies. Areas covered: This review illuminates those investigational drugs and cell therapies that are currently in early phase clinical trials for the treatment of DLBCL. New small molecules that modulate the pathways involved in the molecular pathogenesis of DLBCL, monospecific and bispecific monoclonal antibodies, drug-immunoconjugates, and cellular therapies are placed under the spotlight. A futuristic perspective concludes the paper. Expert opinion: A precision medicine strategy based on robust molecular predictors of outcome is desirable in the development of investigational small molecules for DLBCL. Novel monoclonal and bispecific antibodies may be offered to (i) relapsed/refractory patients ineligible for CAR-T cells because of comorbidities, and (ii) younger patients before CAR-T cell infusion to reduce a high tumor burden. A focus on the optimal sequencing of the emerging DLBCL drugs is appropriate and necessary.
TL;DR: In this paper, the authors reviewed the development of the HIF-2 alpha inhibitor, MK-6482, and discussed preliminary results of ongoing phase I/II studies in renal cell carcinoma (RCC) and Von Hippel-Lindau (VHL) disease.
Abstract: Introduction Von Hippel-Lindau (VHL) disease is an inherited autosomal dominant syndrome caused by a germline mutation and/or deletion of the VHL gene. Inappropriate hypoxia-inducible factor (HIF)-mediated transcription of proangiogenic and metabolic genes leads to the development of tumors and cysts in multiple organs. Surgery is a standard treatment for localized tumors with a risk of metastasis or organ dysfunction. Repeated surgeries cause substantial morbidity and have a major impact on quality of life. There is an urgent need to develop effective and safe systemic treatments for VHL disease manifestations. The small-molecule HIF 2 alpha inhibitor MK-6482 (belzutifan) has demonstrated significant efficacy in VHL disease related renal cell carcinomas, hemangioblastomas, and pancreatic neuroendocrine tumors while demonstrating an acceptable safety profile. Areas covered This paper reviews the development of the HIF-2 alpha inhibitor, MK-6482, and discusses preliminary results of ongoing phase I/II studies in renal cell carcinoma (RCC) and VHL disease. An examination of ongoing clinical development of MK-6482 and perspectives on potential future developments and challenges are offered. Expert opinion Because of its favorable safety profile, its clear efficacy in VHL disease, promising findings in sporadic, advanced RCC, and convenient oral formulation, MK-6482 is expected to become a leading treatment for VHL disease. Among other currently available oral agents, we believe that MK-6482 will be a preferred treatment for VHL-associated RCC.
TL;DR: In this article, a narrative review summarizes data from head-to-head comparisons of emerging non-steroidal MRAs with older steroidal MRAs, including pharmacological characteristics, pharmacokinetic properties, clinical outcomes, and safety.
Abstract: INTRODUCTION Mineralocorticoid receptor (MR) antagonists (MRAs) provide cardiorenal protection. However steroidal MRAs might induce hyperkalemia and sex hormone-related adverse effects. Several novel non-steroidal MRAs are being developed that are highly selective for the MR and may have an improved safety profile. AREAS COVERED This narrative review summarizes data from head-to-head comparisons of emerging non-steroidal MRAs with older steroidal MRAs, including pharmacological characteristics, pharmacokinetic properties, clinical outcomes, and safety, and highlights similarities and differences between emerging agents and established steroidal MRAs. EXPERT OPINION Head-to-head comparisons in phase 2 trials suggest that the new non-steroidal MRAs exhibit at least equivalent efficacy to steroidal MRAs but may have a better safety profile in patients with heart failure and/or kidney disease. When also taking into account data from recent phase 3 placebo-controlled trials, these novel non-steroidal MRAs have the potential to provide a cardiorenal benefit above that of current optimized standard-of-care treatment in a high-risk population with reduced renal function, with a low risk of hyperkalemia. To optimize therapy, further research is needed to clarify the molecular differences in the mode of action of non-steroidal MRAs versus steroidal MRA, and biomarkers that are predictive of MRA response need to be identified and validated.
TL;DR: In this paper, a review discusses the rationale, preclinical evidence, first clinical e-evidence, and pending issues concerning new promising therapeutic options that are under investigation in SSc.
Abstract: Introduction: Systemic sclerosis (SSc), also known as scleroderma, is a complex orphan disease characterized by early inflammatory features, vascular hyper-reactivity, and fibrosis of the skin and internal organs. Although substantial progress has been made in the understanding of the pathogenesis of SSc, there is still no disease-modifying drug that could significantly impact the natural history of the disease.Areas covered: This review discusses the rationale, preclinical evidence, first clinical eevidence,and pending issues concerning new promising therapeutic options that are under investigation in SSc. The search strategy was based on PubMed database and clinical trial.gov, highlighting recent key pathogenic aspects and phase I or II trials of investigational drugs in SSc.Expert opinion: The identification of new molecular entities that potentially impact inflammation and fibrosis may constitute promising options for a disease modifying-agent in SSc. The early combinations of antifibrotic drugs (such as pirfenidone) with immunomodulatory agents (such as mycophenolate mofetil) may also participate to achieve such a goal. A more refined stratification of patients, based on clinical features, molecular signatures, and identification of subpopulations with distinct clinical trajectories, may also improve management strategies in the future.
TL;DR: In this article, the authors explored the preclinical development and clinical pharmacokinetics from early phase clinical studies (2015 or later) of novel oral selective estrogen receptor degrader (SERD) including giredestrant, amcenestant, camizestants, elacestrants, and rintodestrants.
Abstract: Introduction The selective estrogen receptor degrader (SERD) and full receptor antagonist provides an important therapeutic option for hormone receptor (HR)-positive breast cancer. Endocrine therapies include tamoxifen, a selective estrogen receptor modulator (SERM), that exhibits receptor agonist and antagonist activity, and aromatase inhibitors that block estrogen biosynthesis but which demonstrate acquired resistance. Fulvestrant, the only currently approved SERD, is limited by poor drug-like properties. A key focus for improving disease management has been development of oral SERDs with optimized target occupancy and potency and superior clinical efficacy. Areas covered Using PubMed, clinicaltrials.gov, and congress websites, this review explored the preclinical development and clinical pharmacokinetics from early phase clinical studies (2015 or later) of novel oral SERDs, including giredestrant, amcenestrant, camizestrant, elacestrant, and rintodestrant. Expert opinion Numerous oral SERDs are in clinical development, aiming to form the core endocrine therapy for HR-positive breast cancer. Through property- and structure-based drug design of estrogen receptor-binding, antagonism, degradation, anti-proliferation, and pharmacokinetic properties, these SERDs have distinct profiles which impact clinical dosing, efficacy, and safety. Assuming preliminary safety and activity data are confirmed in phase 3 trials, these promising agents could further improve the management, outcomes, and quality of life in HR-positive breast cancer.
TL;DR: Angelman syndrome is a rare genetic neurodevelopmental disorder, caused by deficiency or abnormal function of the maternal ubiquitin protein-ligase known as UBE3A as discussed by the authors.
Abstract: Introduction: Angelman syndrome is a rare genetic neurodevelopmental disorder, caused by deficiency or abnormal function of the maternal ubiquitin protein-ligase E3A, known as UBE3A, in the central...
TL;DR: Fezolinetant as mentioned in this paper is the most advanced neurokinin-3 receptor (NK3R) antagonist in terms of stage of clinical development for menopause-associated vasomotor symptoms.
Abstract: Introduction: Although international clinical practice guidelines recognize a continued role for menopausal hormone therapy (HT), particularly for symptomatic women <60 years of age or within 10 years of menopause, safety and tolerability concerns have discouraged HT use due to potential links with a perceived increased risk of hormone-dependent cancers, and an established risk of stroke and venous thromboembolism. There is therefore a need for safe, effective non-hormonal therapy for relief of menopausal vasomotor symptoms (VMS).Areas covered: This narrative review summarizes the dataset accrued for fezolinetant, a neurokinin-3 receptor (NK3R) antagonist in clinical development for menopause-associated VMS.Expert opinion: Altered signaling in neuroendocrine circuits at menopause leads to VMS wherein NK3R activity plays a key role to modulate the thermoregulatory center in a manner conducive to triggering the 'hot flash' response. Thus, a new generation of NK3R antagonists has entered clinical development to specifically target the mechanistic basis of VMS. Fezolinetant is the most advanced NK3R antagonist in terms of stage of clinical development. Results to date have demonstrated rapid and substantial reduction in VMS frequency and severity and associated improvements in health-related quality of life. NK3R antagonists offer a non-hormonal alternative to HT for the treatment of menopause-related VMS.
University of Southern California1, Eastern Virginia Medical School2, Anschutz Medical Campus3, Washington University in St. Louis4, Seton Hall University5, University of Texas Health Science Center at San Antonio6, University of Modena and Reggio Emilia7, Autonomous University of Barcelona8, University of Porto9, Columbia University10
TL;DR: In this article, the authors search the major national registries, pubmed.org, and the preprint servers for all ongoing, completed and published trial results and find 111 publications reporting findings on 14 classes of agents, and 9 vaccines.
Abstract: Background: COVID-19 has several overlapping phases. Treatments to date have focused on the late stage of disease in hospital. Yet, the pandemic is by propagated by the viral phase in out-patients. The current public health strategy relies solely on vaccines to prevent disease.Methods: We searched the major national registries, pubmed.org, and the preprint servers for all ongoing, completed and published trial results.Results: As of 2/15/2021, we found 111 publications reporting findings on 14 classes of agents, and 9 vaccines. There were 62 randomized controlled studies, the rest retrospective observational analyses. Only 21 publications dealt with outpatient care. Remdesivir and high titer convalescent plasma have emergency use authorization for hospitalized patients in the U.S.A. There is also support for glucocorticoid treatment of the COVID-19 respiratory distress syndrome. Monoclonal antibodies are authorized for outpatients, but supply is inadequate to treat all at time of diagnosis. Favipiravir, ivermectin, and interferons are approved in certain countries.Expert Opinion: Vaccines and antibodies are highly antigen specific, and new SARS-Cov-2 variants are appearing. We call on public health authorities to authorize treatments with known low-risk and possible benefit for outpatients in parallel with universal vaccination.
TL;DR: A large number of the copper-containing materials used in mining and smelting are non-volatile, meaning that they do not have to be pure copper to be considered as a mining material.
Abstract: Copper serves as a structural and catalytic cofactor for a variety of enzymes in aerobic organisms. Though present in trace amounts, copper is essential for numerous biochemical processes including...
TL;DR: In this paper, the authors reviewed the current standard of therapy for intrahepatic cholangiocarcinoma (iCCA), the genomic targets, and the role of FGFR inhibitors in developing the treatment landscape.
Abstract: Introduction: The increasing availability of next-generation DNA sequencing (NGS) opens the opportunity to tailor therapies to potential targets. Intrahepatic cholangiocarcinoma (iCCA) has the most actionable genomic targets of the hepatobiliary malignancies, including mutations in Isocitrate Dehydrogenase (IDH) and Fibroblast Growth Factor Receptor (FGFR), particularly FGFR2. With the recent accelerated approval of pemigatinib and several trials currently underway, FGFR2 inhibition will set the mold for tailored therapies in hepatobiliary cancer.Areas covered: We review the current standard of therapy for iCCA, the genomic targets, and the role of FGFR inhibitors in developing the treatment landscape. The FGFR mechanism of actionand use of IDH1/2 inhibition and immunotherapy in iCCA are also discussed. We queried the PubMed and ClinicalTrials.gov databases, along with conference proceedings for relevant data.Expert opinion: While more mature data are needed from the trials in progress, currently published analyses show survival benefit with FGFR2 inhibitors in patients positive for FGFR2 fusion who have failed the standard of care. Infigratinib, futibatinib, pemigatinib and derazantinib have all demonstrated promising activity iCCA patients harboring FGFR2 fusion. Eventually, head-to-head trials will be needed to fully understand the benefits of each agent and the role of reversible versus irreversible FGFR2 inhibitors.
TL;DR: In this paper, the authors demonstrate that cancer neoantigens can be recognized by the immune system through protein sequences with novel amino acid sequences that can be identified by the human immune system.
Abstract: Derived from genetic alterations, cancer neoantigens are proteins with novel amino acid sequences that can be recognized by the immune system. Recent evidence demonstrates that cancer neoantigens r...
TL;DR: In this article, a subset of patients experienced resistance and/or intolera drug resistance to tyrosine kinase inhibitors (TKIs) in chronic myeloid leukemia (CML) patients.
Abstract: Introduction: Tyrosine kinase inhibitors (TKIs) have drastically changed the outcome of chronic myeloid leukemia (CML) patients. However, a subset of patients experienced resistance and/or intolera...
TL;DR: PARP inhibitors can obtain an important role in making a personalized therapeutic program in the case of first-line, neoadjuvant, platinum-sensitive, and resistant high-grade serous OC treatment, including approved as well as currently investigated drugs.
Abstract: Poly (ADP-ribose) polymerase (PARP) inhibitors are being developed in maintenance and recurrence treatment settings of epithelial ovarian cancers (EOCs) with BRCA 1–2 gene mutation. PARP inhibitors...
TL;DR: The preclinical science leading to the creation of the AE37 vaccine is described in detail and the potential of this agent in breast and prostate cancer patient subsets along with other malignancies is examined.
Abstract: HER2 is a prevalent growth factor in a variety of malignancies, most prominently breast cancer. Over-expression has been correlated with the poorest overall survival and has been the target of succ...
TL;DR: The increased understanding of GIST and advances in the development of molecular-targeted drugs led to the introduction of ripretinib and avapritinib, and N TRK inhibitors became available for ultrarare NTRK fusions.
Abstract: Introduction: Discovery of oncogenic mutations in the KIT and PDGFRA tyrosine kinase receptor was a crucial step for the development of tyrosine kinase inhibitors (TKIs). Since then, GIST became a model for the development of molecular-targeted therapy, which led to dramatically improved median overall survival of advanced GIST. Still, further progress is needed after third-line or for TKI resistant mutations. Areas covered: In this review, after a brief introduction on imatinib, sunitinib, and regorafenib, an overview of TKIs that was evaluated beyond these drugs is provided, with a main focus on the novel approved TKIs. Expert opinion: Combination therapies have thus far not fulfilled their promise in GIST, nor did immunotherapy. Increased understanding of GIST and advances in the development of molecular-targeted drugs led to the introduction of ripretinib and avapritinib. Furthermore, NTRK inhibitors became available for ultrarare NTRK fusions. Solutions for NF1 and BRAF mutated and SDH-deficient GIST are still to be awaited. This all underlines the need for adequate molecular profiling of high-risk GISTs before treatment is started. Possibly by using circulating tumor DNA in the future, targeting resistance mutations with specific drugs along the course of the disease would be easier, avoiding multiple tumor biopsies.
TL;DR: This review provides a brief background on TLS and its role in cancer and discusses the identification and development of inhibitors that target various TLS DNA polymerases or key protein–protein interactions (PPIs) in the TLS machinery.
Abstract: Introduction: Translesion synthesis (TLS) is a DNA damage tolerance mechanism that replaces the replicative DNA polymerase with a specialized, low-fidelity TLS DNA polymerase that can copy past DNA lesions during active replication. Recent studies have demonstrated a primary role for TLS in replicating past DNA lesions induced by first-line genotoxic agents, resulting in decreased efficacy and acquired chemoresistance. With this in mind, targeting TLS as a combination strategy with first-line genotoxic agents has emerged as a promising approach to develop a new class of anti-cancer adjuvant agents. Areas covered: In this review, we provide a brief background on TLS and its role in cancer. We also discuss the identification and development of inhibitors that target various TLS DNA polymerases or key protein-protein interactions (PPIs) in the TLS machinery. Expert opinion: TLS inhibitors have demonstrated initial promise; however, their continued study is essential to more fully understand the clinical potential of this emerging class of anti-cancer chemotherapeutics. It will be important to determine whether a specific protein involved in TLS is an optimal target. In addition, an expanded understanding of what current genotoxic chemotherapies synergize with TLS inhibitors will guide the clinical strategies for devising combination therapies.
TL;DR: An enhanced understanding of the various components of the CCA TME is essential in the effort to develop novel biomarkers for patient stratification as well as combination therapeutic strategies that target the tumor plus the TME.
Abstract: Introduction: Cholangiocarcinomas (CCAs) are biliary epithelial tumors with rising incidence over the past 3 decades. Early diagnosis of CCAs remains a significant challenge and the majority of pat...