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1.
How I treat Waldenström macroglobulinemia.
Dimopoulos, MA, Kastritis, E
Blood. 2019;(23):2022-2035
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Abstract
Waldenström macroglobulinemia (WM) is an uncommon lymphoma characterized by the infiltration of the bone marrow by clonal lymphoplasmacytic cells that produce monoclonal immunoglobulin M (IgM). The disease may have an asymptomatic phase, or patients may present with symptoms and complications resulting from marrow or other tissue infiltration, or from physicochemical or immunological properties of the monoclonal IgM. Diagnosis of WM has been clearly defined, and genetic testing for somatic mutation of MYD88L265P is a useful tool for differential diagnosis from other conditions. Specific criteria that define symptomatic disease that needs treatment offer clinical guidance. The treatment of WM has evolved rapidly, with treatment options that include anti-CD20 monoclonal antibody-based combinations and BTK inhibitors. The choice of therapy is based on the need for rapid disease control, presence of specific disease complications, and patient's age. With the use of BTK inhibitors, the use of continuous therapy has been introduced as another option over fixed-duration chemoimmunotherapy. In this review, we focus on different clinical scenarios and discuss treatment options, based on the available data.
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Lenvatinib complementary with radioiodine therapy for patients with advanced differentiated thyroid carcinoma: case reports and literature review.
Sheu, NW, Jiang, HJ, Wu, CW, Chiang, FY, Chiou, HC, Hsiao, PJ
World journal of surgical oncology. 2019;(1):84
Abstract
BACKGROUND The prognosis for patients with advanced differentiated thyroid carcinoma (ADTC) with disseminated distant metastases is very poor. Tyrosine kinase inhibitors targeting tumor angiogenesis have been shown to improve progression-free survival in patients with advanced thyroid carcinoma and progressive radioiodine-refractory thyroid carcinoma. Tyrosine kinase inhibitor has been reported as a successful neoadjuvant for total thyroidectomy to reduce tumor burden. However, the special indications for prompt treatment with lenvatinib as a rescue therapy to reduce tumor burden and prolong a durable response to radioiodine therapy have not been explored. CASE PRESENTATION Here, we present two ADTC cases with distant metastases who were effectively treated by total thyroidectomy combined with lenvatinib to prolong a durable response to radioiodine therapy. Case 1 was a 66-year-old male diagnosed with ADTC and disseminated brain, lung, and bone metastases. Lenvatinib was initiated via compassionate access because of rapidly progressive tumor growth even after second doses of radioiodine therapy and external beam radiation therapy for his brain metastases. The result was a durable response to lenvatinib, slowing progressive tumor growth for 3 years and allowing a third course of radioiodine therapy to treat the bone metastases. Case 2 was a 45-year-old male diagnosed with ADTC and diffuse disseminated lung metastases. Respiratory failure ensued after total thyroidectomy, requiring mandatory support by respirator. Lenvatinib was started as a rescue therapy to reduce tumor burden rapidly. The patient was successfully weaned off the respirator only 1 week after using lenvatinib. The patient was then maintained on a low dose of lenvatinib, allowing three subsequent courses of radioiodine therapy. Currently, his lung metastasis remains well controlled with decreased lung infiltrating nodules and the patient can tolerate exercise well. CONCLUSION Our case experience indicated that lenvatinib has significant value as salvage therapy, reducing tumor burden, producing a durable response and maintaining quality of life. For ADTC patients with progressive life-threatening metastases, our experience suggests that lenvatinib treatment can be used as an urgent rescue therapy as well as a complement to radioiodine therapy to improve tumor eradication.
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3.
Computational Prediction of the Site(s) of Metabolism and Binding Modes of Protein Kinase Inhibitors Metabolized by CYP3A4.
Nair, PC, McKinnon, RA, Miners, JO
Drug metabolism and disposition: the biological fate of chemicals. 2019;(6):616-631
Abstract
Protein kinase inhibitors (KIs), which are mainly biotransformed by CYP3A4-catalyzed oxidation, represent a rapidly expanding class of drugs used primarily for the treatment of cancer. Ligand- and structure-based methods were applied here to investigate whether computational approaches may be used to predict the site(s) of metabolism (SOM) of KIs and to identify amino acids within the CYP3A4 active site involved in KI binding. A data set of the experimentally determined SOMs of 31 KIs known to undergo biotransformation by CYP3A4 was collated. The structure-based (molecular docking) approach employed three CYP3A4 X-ray crystal structures to account for structural plasticity of this enzyme. Docking pose and SOM predictivity were influenced by the X-ray crystal template used for docking and the scoring function used for ranking binding poses. The best prediction of SOM (77%) was achieved using the substrate (bromoergocryptine)-bound X-ray crystal template together with the potential of mean force score. Binding interactions of KIs with CYP3A4 active site residues were generally similar to those observed for other substrates of this enzyme. The ligand-based molecular superposition approach, using bromoergocryptine from the X-ray cocrystal structure as a template, poorly predicted (42%) the SOM of KIs, although predictivity improved to 71% when the docked conformation of sorafenib was used as the template. Among the web-based approaches examined, all web servers provided excellent predictivity, with one web server predicting the SOM of 87% of the data set molecules. Computational approaches may be used to predict the SOM of KIs, and presumably other classes of CYP3A4 substrates, but predictivity varies between methods.
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4.
Rapid Screen for Tyrosine Kinase Inhibitor Resistance Mutations and Substrate Specificity.
Taft, JM, Georgeon, S, Allen, C, Reckel, S, DeSautelle, J, Hantschel, O, Georgiou, G, Iverson, BL
ACS chemical biology. 2019;(9):1888-1895
Abstract
We present a rapid and high-throughput yeast and flow cytometry based method for predicting kinase inhibitor resistance mutations and determining kinase peptide substrate specificity. Despite the widespread success of targeted kinase inhibitors as cancer therapeutics, resistance mutations arising within the kinase domain of an oncogenic target present a major impediment to sustained treatment efficacy. Our method, which is based on the previously reported YESS system, recapitulated all validated BCR-ABL1 mutations leading to clinical resistance to the second-generation inhibitor dasatinib, in addition to identifying numerous other mutations which have been previously observed in patients, but not yet validated as drivers of resistance. Further, we were able to demonstrate that the newer inhibitor ponatinib is effective against the majority of known single resistance mutations, but ineffective at inhibiting many compound mutants. These results are consistent with preliminary clinical and in vitro reports, indicating that mutations providing resistance to ponatinib are significantly less common; therefore, predicting ponatinib will be less susceptible to clinical resistance relative to dasatinib. Using the same yeast-based method, but with random substrate libraries, we were able to identify consensus peptide substrate preferences for the SRC and LYN kinases. ABL1 lacked an obvious consensus sequence, so a machine learning algorithm utilizing amino acid covariances was developed which accurately predicts ABL1 kinase peptide substrates.
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5.
Potential role of cyclin-dependent kinase 4/6 inhibitors in the treatment of squamous cell carcinoma of the head and neck.
van Caloen, G, Machiels, JP
Current opinion in oncology. 2019;(3):122-130
Abstract
PURPOSE OF REVIEW Human papillomavirus (HPV)-negative squamous cell carcinoma of the head and neck (SCCHN) is mainly driven by genetic aberrations involved in the cell cycle pathway resulting in cyclin-dependent kinase (CDK) 4 and 6 activation. This supports the investigation of the activity of CDK4/6 inhibitors in this disease. We review the therapeutic potential of CDK4/6 inhibitors in SCCHN. RECENT FINDINGS CDK4/6 inhibitors in monotherapy have demonstrated cytostatic activity in HPV-negative SCCHN. Combination with epidermal growth factor inhibitors, with phosphatidylinositol-3-kinase/protein kinase B/mammalian target of rapamycin pathways inhibitors or with immunotherapy, have shown promising preclinical efficacy. No strong predictive biomarkers of response or resistance have been firmly identified.Phase I clinical trials have demonstrated that palbociclib or ribociclib in combination with cetuximab is well tolerated. A phase II single-arm trial combining palbociclib/cetuximab has shown promising results. SUMMARY Inhibition of CDK4/6 represents a new potential treatment for HPV-negative SCCHN patients. Randomized clinical trials that investigate these compounds in an unbiased manner are needed to fully evaluate their efficacy. However, it is unlikely that all the patients will benefit from this new approach. To determine a molecular profile/phenotype that will predict CDK4/6 inhibitor activity, researchers will have to take into account simultaneously occurring events in the cyclin-D/CDK4/CDK6/retinoblastoma and associated pathways.
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Combined hepatocellular-cholangiocarcinoma successfully treated with sorafenib: case report and review of the literature.
Futsukaichi, Y, Tajiri, K, Kobayashi, S, Nagata, K, Yasumura, S, Takahara, T, Minemura, M, Yasuda, I
Clinical journal of gastroenterology. 2019;(2):128-134
Abstract
Sorafenib, a multiple kinase inhibitor, has been established as first-line standard systemic chemotherapy for patients with advanced hepatocellular carcinoma (HCC). We encountered a patient with combined hepatocellular and cholangiocarcinoma (CHC) who achieved complete remission in response to sorafenib treatment. A 58-year old man with hepatitis C virus (HCV)-induced liver cirrhosis was diagnosed with CHC in segments 6th and 7th of the liver and underwent partial surgical resection. Three months later, CHC recurred as metastases at multiple intrahepatic sites, lymph nodes, and bones, making surgery impossible. Treatment with sorafenib was initiated at 400 mg b.i.d., later reduced to 400 mg/day. After 6 months of sorafenib administration, he no longer showed abnormal uptake on fluorodeoxyglucose positron emission tomography. He was continued on sorafenib for 2.5 years, but later discontinued due to adverse events. He has shown no evidence of tumor recurrence more than 1 year after sorafenib discontinuation. His HCV was eradicated by direct-acting antivirals, and he remains in good health.
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7.
SLC36A1-mTORC1 signaling drives acquired resistance to CDK4/6 inhibitors.
Yoshida, A, Bu, Y, Qie, S, Wrangle, J, Camp, ER, Hazard, ES, Hardiman, G, de Leeuw, R, Knudsen, KE, Diehl, JA
Science advances. 2019;(9):eaax6352
Abstract
The cyclin-dependent kinase 4/6 (CDK4/6) kinase is dysregulated in melanoma, highlighting it as a potential therapeutic target. CDK4/6 inhibitors are being evaluated in trials for melanoma and additional cancers. While beneficial, resistance to therapy is a concern, and the molecular mechanisms of such resistance remain undefined. We demonstrate that reactivation of mammalian target of rapamycin 1 (mTORC1) signaling through increased expression of the amino acid transporter, solute carrier family 36 member 1 (SLC36A1), drives resistance to CDK4/6 inhibitors. Increased expression of SLC36A1 reflects two distinct mechanisms: (i) Rb loss, which drives SLC36A1 via reduced suppression of E2f; (ii) fragile X mental retardation syndrome-associated protein 1 overexpression, which promotes SLC36A1 translation and subsequently mTORC1. Last, we demonstrate that a combination of a CDK4/6 inhibitor with an mTORC1 inhibitor has increased therapeutic efficacy in vivo, providing an important avenue for improved therapeutic intervention in aggressive melanoma.
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8.
Emerging Role of Multikinase Inhibitors in Desmoid Tumor Management.
Penel, N, Ryckewaert, T, Le Deley, MC
American journal of clinical oncology. 2019;(12):958
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9.
Role and relevance of quality indicators in the selection of first-line treatment of patients with metastatic renal cell carcinoma: a position paper of the MeetURO Group.
Procopio, G, Pignata, S, Altavilla, A, Attademo, L, De Lisi, D, Verzoni, E, De Giorgi, U, Santini, D
Future oncology (London, England). 2019;(22):2657-2666
Abstract
Tyrosine kinase inhibitors still play a very important role in the treatment of metastatic renal cell carcinoma despite a continuously changing scenario, in which immunotherapy and several combination-based approaches are also available. In this light, patient-reported outcomes and health-related quality of life are important factors in the selection of the best first-line treatment. This Review focuses on the existing evidence on patient-reported outcomes and health-related quality of life with several tyrosine kinase inhibitors (pazopanib, sunitinib, cabozantinib and tivozanib) used as first-line treatment for metastatic renal cell carcinoma.
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10.
Signaling alterations caused by drugs and autophagy.
Dent, P, Booth, L, Poklepovic, A, Hancock, JF
Cellular signalling. 2019;:109416
Abstract
Autophagy is an evolutionary conserved process that recycles cellular materials in times of nutrient restriction to maintain viability. In cancer therapeutics, the role of autophagy in response to multi-kinase inhibitors, alone or when combined with histone deacetylase (HDAC) inhibitors acts, generally, to facilitate the killing of tumor cells. Furthermore, the formation of autophagosomes and subsequent degradation of their contents can reduce the expression of HDAC proteins themselves as well as of other signaling regulatory molecules such as protein chaperones and mutated RAS proteins. Reduced levels of HDAC6 causes the acetylation and inactivation of heat shock protein 90, and, together with reduced expression of the chaperones HSP70 and GRP78, generates a strong endoplasmic reticulum (ER) stress response. Prolonged intense ER stress signaling causes tumor cell death. Reduced expression of HDACs 1, 2 and 3 causes the levels of programed death ligand 1 (PD-L1) to decline and the expression of Class I MHCA to increase which correlates with elevated immunogenicity of the tumor cells in vivo. This review will specifically focus on the downstream implications that result from autophagic-degradation of HDACs, RAS and protein chaperones.