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Translational Pediatrics Apr 2014Four out of five children diagnosed with cancer can be cured with contemporary cancer therapy. This represents a dramatic improvement since 50 years ago when the cure... (Review)
Review
Four out of five children diagnosed with cancer can be cured with contemporary cancer therapy. This represents a dramatic improvement since 50 years ago when the cure rate of childhood cancer was <25% in the pre-chemotherapy era. Over the past ten years, while improvement in overall survival (OS) has been marginal, progress in pediatric oncology lies with adopting risk-adapted therapeutic approach. This has been made possible through identifying clinical and biologic prognostic factors with rigorous research and stratifying patients using these risk factors, and subsequently modifying therapy according to risk group assignment. This review provides a perspective for eight distinct pediatric malignancies, in which significant advances in treatment were made in the last decade and are leading to changes in standard of care. This includes four hematologic malignancies [acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), non-Hodgkin lymphoma (NHL) and Hodgkin lymphoma (HL)] and four solid tumors [medulloblastoma (MB), low grade glioma (LGG), neuroblastoma (NB) and Ewing sarcoma (ES)]. Together, they comprise 60% of childhood cancer. Improved patient outcome is not limited to better survival, but encompasses reducing both short and long-term treatment-related complications which is as important as cure, given the majority of childhood cancer patients will become long-term survivors. Risk-adapted approach allows treatment intensification in the high-risk cohort while therapy can be de-escalated in the low-risk to minimize toxicity and late sequelae without compromising survival. Advances in medical research technology have also led to a rapid increase in the understanding of the genetics of childhood cancer in the last decade, facilitating identification of molecular targets that can potentially be exploited for therapeutic benefits. As we move into the era of targeted therapeutics, searching for novel agents that target specific genetic lesions becomes a major research focus. We provide an overview of seven novel agents (bevacizumab, bortezomib, vorinostat, sorafenib, tipifarnib, erlotinib and mTOR inhibitors), which have been most frequently pursued in childhood cancers in the last decade, as well as reporting the progress of clinical trials involving these agents.
PubMed: 26835334
DOI: 10.3978/j.issn.2224-4336.2014.02.01 -
Molecular Cancer Dec 2022Inactivation of the Hippo pathway promotes Yap nuclear translocation, enabling execution of a transcriptional program that induces tissue growth. Genetic lesions of...
BACKGROUND
Inactivation of the Hippo pathway promotes Yap nuclear translocation, enabling execution of a transcriptional program that induces tissue growth. Genetic lesions of Hippo intermediates only identify a minority of cancers with illegitimate YAP activation. Yap has been implicated in resistance to targeted therapies, but the mechanisms by which YAP may impact adaptive resistance to MAPK inhibitors are unknown.
METHODS
We screened 52 thyroid cancer cell lines for illegitimate nuclear YAP localization by immunofluorescence and fractionation of cell lysates. We engineered a doxycycline (dox)-inducible thyroid-specific mouse model expressing constitutively nuclear YAP, alone or in combination with endogenous expression of either Hras or Braf. We also generated cell lines expressing dox-inducible sh-miR-E-YAP and/or YAP. We used cell viability, invasion assays, immunofluorescence, Western blotting, qRT-PCRs, flow cytometry and cell sorting, high-throughput bulk RNA sequencing and in vivo tumorigenesis to investigate YAP dependency and response of BRAF-mutant cells to vemurafenib.
RESULTS
We found that 27/52 thyroid cancer cell lines had constitutively aberrant YAP nuclear localization when cultured at high density (NU-YAP), which rendered them dependent on YAP for viability, invasiveness and sensitivity to the YAP-TEAD complex inhibitor verteporfin, whereas cells with confluency-driven nuclear exclusion of YAP (CYT-YAP) were not. Treatment of BRAF-mutant thyroid cancer cells with RAF kinase inhibitors resulted in YAP nuclear translocation and activation of its transcriptional output. Resistance to vemurafenib in BRAF-mutant thyroid cells was driven by YAP-dependent NRG1, HER2 and HER3 activation across all isogenic human and mouse thyroid cell lines tested, which was abrogated by silencing YAP and relieved by pan-HER kinase inhibitors. YAP activation induced analogous changes in BRAF melanoma, but not colorectal cells.
CONCLUSIONS
YAP activation in thyroid cancer generates a dependency on this transcription factor. YAP governs adaptive resistance to RAF kinase inhibitors and induces a gene expression program in BRAF-mutant cells encompassing effectors in the NRG1 signaling pathway, which play a central role in the insensitivity to MAPK inhibitors in a lineage-dependent manner. HIPPO pathway inactivation serves as a lineage-dependent rheostat controlling the magnitude of the adaptive relief of feedback responses to MAPK inhibitors in BRAF- cancers.
Topics: Humans; Animals; Mice; Thyroid Neoplasms; raf Kinases
PubMed: 36476495
DOI: 10.1186/s12943-022-01676-9 -
Journal of Neuro-oncology Jan 2018Recurrent glioblastoma (GBM) has a very low 6-month progression free survival (PFS) with currently available treatments. Combination chemotherapy to target multiple cell...
Recurrent glioblastoma (GBM) has a very low 6-month progression free survival (PFS) with currently available treatments. Combination chemotherapy to target multiple cell signaling pathways is currently being investigated in order to improve prognosis for recurrent disease. The purpose of this phase I study was to determine the maximum tolerated dose (MTD) for the combination of tipifarnib and sorafenib for the treatment of recurrent GBM. Patients with pathologically proven WHO grade IV GBM and radiographically proven tumor recurrence were eligible for this study. Treatments included sorafenib at twice daily and escalating dosages of tipifarnib. Dose-limiting toxicity (DLT) was determined over the first 28-days of treatments, and the MTD was determined in a 3 + 3 study design. We enrolled 24 patients, and 21 patients completed the MTD period. The study was stopped early with no MTD determination for excessive toxicities. The last dose level reached was sorafenib at 200 mg twice a day and tipifarnib 100 mg twice a day on an alternating week schedule. The DLTs included diarrhea, lipase elevation, hypophosphatemia, and arthralgia. The combination of sorafenib and tipifarnib has excessive toxicities and full single agent dosages could not be achieved in combination.
Topics: Adult; Aged; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Brain Neoplasms; Female; Glioblastoma; Humans; Male; Maximum Tolerated Dose; Middle Aged; Neoplasm Recurrence, Local; Quinolones; Sorafenib; Treatment Outcome
PubMed: 28988377
DOI: 10.1007/s11060-017-2624-4 -
Molecular Cancer Therapeutics Sep 2020Tipifarnib is a potent and highly selective inhibitor of farnesyltransferase (FTase). FTase catalyzes the posttranslational attachment of farnesyl groups to signaling...
Tipifarnib is a potent and highly selective inhibitor of farnesyltransferase (FTase). FTase catalyzes the posttranslational attachment of farnesyl groups to signaling proteins that are required for localization to cell membranes. Although all RAS isoforms are FTase substrates, only HRAS is exclusively dependent upon farnesylation, raising the possibility that HRAS-mutant tumors might be susceptible to tipifarnib-mediated inhibition of FTase. Here, we report the characterization of tipifarnib activity in a wide panel of -mutant and wild-type head and neck squamous cell carcinoma (HNSCC) xenograft models. Tipifarnib treatment displaced both mutant and wild-type HRAS from membranes but only inhibited proliferation, survival, and spheroid formation of -mutant cells. , tipifarnib treatment induced tumor stasis or regression in all six -mutant xenografts tested but displayed no activity in six wild-type patient-derived xenograft (PDX) models. Mechanistically, drug treatment resulted in the reduction of MAPK pathway signaling, inhibition of proliferation, induction of apoptosis, and robust abrogation of neovascularization, apparently via effects on both tumor cells and endothelial cells. Bioinformatics and quantitative image analysis further revealed that FTase inhibition induces progressive squamous cell differentiation in tipifarnib-treated HNSCC PDXs. These preclinical findings support that represents a druggable oncogene in HNSCC through FTase inhibition by tipifarnib, thereby identifying a precision therapeutic option for HNSCCs harboring mutations.
Topics: Alkyl and Aryl Transferases; Animals; Antineoplastic Agents; Cell Proliferation; Cell Survival; Head and Neck Neoplasms; Humans; MAP Kinase Signaling System; Male; Mice; Mutation; Precision Medicine; Prenylation; Proto-Oncogene Proteins p21(ras); Quinolones; Sequence Analysis, RNA; Squamous Cell Carcinoma of Head and Neck
PubMed: 32727882
DOI: 10.1158/1535-7163.MCT-19-0958 -
Cancer Research Apr 2023The survival rate for patients with head and neck cancer (HNC) diagnosed with cervical lymph node (cLN) or distant metastasis is low. Genomic alterations in the HRAS...
UNLABELLED
The survival rate for patients with head and neck cancer (HNC) diagnosed with cervical lymph node (cLN) or distant metastasis is low. Genomic alterations in the HRAS oncogene are associated with advanced tumor stage and metastasis in HNC. Elucidation of the molecular mechanisms by which mutated HRAS (HRASmut) facilitates HNC metastasis could lead to improved treatment options for patients. Here, we examined metastasis driven by mutant HRAS in vitro and in vivo using HRASmut human HNC cell lines, patient-derived xenografts, and a novel HRASmut syngeneic model. Genetic and pharmacological manipulations indicated that HRASmut was sufficient to drive invasion in vitro and metastasis in vivo. Targeted proteomic analysis showed that HRASmut promoted AXL expression via suppressing the Hippo pathway and stabilizing YAP1 activity. Pharmacological blockade of HRAS signaling with the farnesyltransferase inhibitor tipifarnib activated the Hippo pathway and reduced the nuclear export of YAP1, thus suppressing YAP1-mediated AXL expression and metastasis. AXL was required for HRASmut cells to migrate and invade in vitro and to form regional cLN and lung metastases in vivo. In addition, AXL-depleted HRASmut tumors displayed reduced lymphatic and vascular angiogenesis in the primary tumor. Tipifarnib treatment also regulated AXL expression and attenuated VEGFA and VEGFC expression, thus regulating tumor-induced vascular formation and metastasis. Our results indicate that YAP1 and AXL are crucial factors for HRASmut-induced metastasis and that tipifarnib treatment can limit the metastasis of HNC tumors with HRAS mutations by enhancing YAP1 cytoplasmic sequestration and downregulating AXL expression.
SIGNIFICANCE
Mutant HRAS drives metastasis of head and neck cancer by switching off the Hippo pathway to activate the YAP1-AXL axis and to stimulate lymphovascular angiogenesis.
Topics: Humans; Proteomics; Transcription Factors; Cell Line, Tumor; Signal Transduction; Head and Neck Neoplasms; Proto-Oncogene Proteins p21(ras)
PubMed: 36753744
DOI: 10.1158/0008-5472.CAN-22-2586 -
Cancer Research Aug 2018Of the three RAS oncoproteins, only HRAS is delocalized and inactivated by farnesyltransferase inhibitors (FTI), an approach yet to be exploited clinically. In this...
Of the three RAS oncoproteins, only HRAS is delocalized and inactivated by farnesyltransferase inhibitors (FTI), an approach yet to be exploited clinically. In this study, we treat mice bearing Hras-driven poorly differentiated and anaplastic thyroid cancers ( ) with the FTI tipifarnib. Treatment caused sustained tumor regression and increased survival; however, early and late resistance was observed. Adaptive reactivation of RAS-MAPK signaling was abrogated by selective RTK (i.e., EGFR, FGFR) inhibitors, but responses were ineffective , whereas combination of tipifarnib with the MEK inhibitor AZD6244 improved outcomes. A subset of tumor-bearing mice treated with tipifarnib developed acquired resistance. Whole-exome sequencing of resistant tumors identified a nonsense mutation and an activating mutation in at high allelic frequency, supporting the on-target effects of the drug. Cell lines modified with these genetic lesions recapitulated tipifarnib resistance This study demonstrates the feasibility of targeting Ras membrane association in cancers and predicts combination therapies that confer additional benefit. Tipifarnib effectively inhibits oncogenic HRAS-driven tumorigenesis and abrogating adaptive signaling improves responses. NF1 and GNAS mutations drive acquired resistance to Hras inhibition, supporting the on-target effects of the drug. .
Topics: Animals; Benzimidazoles; Carcinogenesis; Cell Differentiation; Cell Line, Tumor; Cell Proliferation; Chromogranins; GTP-Binding Protein alpha Subunits, Gs; Humans; Mice; Mutation; Neurofibromin 1; Proto-Oncogene Proteins p21(ras); Quinolones; Thyroid Neoplasms; Xenograft Model Antitumor Assays
PubMed: 29760048
DOI: 10.1158/0008-5472.CAN-17-1925 -
Expert Opinion on Investigational Drugs May 2010Acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) incidence in the United States increases with age. Given the progressive ageing of the general... (Review)
Review
IMPORTANCE OF THE FIELD
Acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) incidence in the United States increases with age. Given the progressive ageing of the general population, incidence of these diseases is likely to continue to rise in the future. There is an acute need for therapeutic developments because of the poor prognosis of these diseases. Since the knowledge of molecular genetics in AML and MDS has expanded recently, targeted therapeutics should offer an exciting new frontier for advancement. Of all the targeted inhibitors developed, tipifarnib represents one of the few compounds with some activity as a single agent.
AREAS COVERED IN THIS REVIEW
Described in this review are the molecular targets of tipifarnib, safety and tolerability of the drug, chemistry, and clinical efficacy in AML.
WHAT THE READER WILL GAIN
The reader will gain a thorough understanding of tipifarnib as it relates to the current and future use of the drug in AML.
TAKE HOME MESSAGE
The future of tipifarnib, along with other molecularly-targeted drugs, lies in achieving a better understanding of leukemia biology and harnessing the activity of this agent using predictive biomarkers for improved patient selection.
Topics: Age Factors; Animals; Antineoplastic Agents; Drug Delivery Systems; Farnesyltranstransferase; Humans; Leukemia, Myeloid, Acute; Myelodysplastic Syndromes; Prognosis; Quinolones
PubMed: 20402600
DOI: 10.1517/13543781003801076 -
FEBS Open Bio May 2021Farnesyltransferase inhibitors (FTIs) suppress tumor aggressiveness in several malignancies by inhibiting Ras signaling. However, treatment of cells with a low dose of...
Farnesyltransferase inhibitors (FTIs) suppress tumor aggressiveness in several malignancies by inhibiting Ras signaling. However, treatment of cells with a low dose of the FTI tipifarnib suppresses the expression of hypoxia-inducible factor-1α (HIF-1α) and results in antitumor effects without inhibiting the Ras pathway. Although we previously reported that elevated HIF-1α expression is associated with an aggressive phenotype in gastric cancer (GC), little is known about the antitumor effects of FTIs on GC. In this study, we examined the relationship between the antitumor effects of low-dose tipifarnib and HIF-1α expression in GC cells. Under normoxic conditions, HIF-1α was expressed only in MKN45 and KATOIII cells. The inhibitory effect of tipifarnib on HIF-1α was observed in HIF-1α-positive cells. Low-dose tipifarnib had antitumor effects only on HIF-1α-positive cells both in vitro and in vivo. Furthermore, low-dose tipifarnib inactivated ras homolog enriched in brain (Rheb)/mammalian target of rapamycin (mTOR) signaling and decreased intracellular reactive oxygen species (ROS) levels in HIF-1α-positive GC cells. Our results that the antitumor effects of low-dose tipifarnib are at least partially mediated through suppression of mTOR signaling and HIF-1α expression via inhibition of Rheb farnesylation and reduction in ROS levels. These findings suggest that low-dose tipifarnib may be capable of exerting an antitumor effect that is dependent on HIF-1α expression in GC cells. Tipifarnib may have potential as a novel therapeutic agent for HIF-1α-expressing GC exhibiting an aggressive phenotype.
Topics: Cell Line, Tumor; Humans; Hypoxia-Inducible Factor 1, alpha Subunit; Quinolones; Reactive Oxygen Species; Signal Transduction; Stomach Neoplasms; TOR Serine-Threonine Kinases
PubMed: 33773069
DOI: 10.1002/2211-5463.13154 -
Cancers Feb 2022Tyrosine kinase inhibitors (TKI) were initially demonstrated as an efficacious treatment for renal cell carcinoma (RCC). However, after a median treatment length of 14...
BACKGROUND
Tyrosine kinase inhibitors (TKI) were initially demonstrated as an efficacious treatment for renal cell carcinoma (RCC). However, after a median treatment length of 14 months, a vast majority of patients develop resistance. This study analyzed a combination therapy of tipifarnib (Tipi) + sunitinib that targeted exosome-conferred drug resistance.
METHODS
786-O, 786-O-SR (sunitinib resistant), A498, A498-SR, Caki-2, Caki-2-SR, and 293T cells were cultured. Exosomes were collected using differential ultracentrifugation. Cell proliferation, Jurkat T cell immune assay, and immunoblot analysis were used for downstream analysis.
RESULTS
SR exosomes treatment displayed a cytotoxic effect on immune cells. This cytotoxic effect was associated with increased expression of PD-L1 on SR exosomes when compared to sunitinib-sensitive (SS) exosomes. Additionally, Tipi treatment downregulated PD-L1 expression on exosomes derived from SR cell lines. Tipi's ability to downregulate PD-L1 in exosomes has a significant application within patients. Exosomes collected from patients with RCC showed increased PD-L1 expression over subjects without RCC. Next, exosome concentrations were then compared after Tipi treatment, with all SS cell lines displaying an even greater reduction. On immunoblot assay, 293T cells showed a dose-dependent increase in Alix with no change in either nSMase or Rab27a. Conversely, all the SS and SR cell lines displayed a decrease in all three markers. After a cell proliferation employed a 48-h treatment on all SS and SR cell lines, the drug combination displayed synergistic ability to decrease tumor growth.
CONCLUSIONS
Tipifarnib attenuates both the exosome endosomal sorting complex required for endosomal sorting complex required for transport (ESCRT)-dependent and ESCRT-independent pathways, thereby blocking exosome biogenesis and secretion as well as downregulating PD-L1 on SS and SR cells.
PubMed: 35205655
DOI: 10.3390/cancers14040903 -
Journal of Hematology & Oncology Jul 2013Myelodysplastic syndromes (MDS) are a group of hematologic disorders characterized by ineffective hematopoiesis that results in reduced blood counts. Although MDS can... (Review)
Review
Myelodysplastic syndromes (MDS) are a group of hematologic disorders characterized by ineffective hematopoiesis that results in reduced blood counts. Although MDS can transform into leukemia, most of the morbidity experienced by these patients is due to chronically low blood counts. Conventional cytotoxic agents used to treat MDS have yielded some encouraging results but are characterized by many adverse effects in the predominantly elderly patient population. Targeted interventions aimed at reversing the bone marrow failure and increasing the peripheral blood counts would be advantageous in this cohort of patients. Studies have demonstrated over-activated signaling of myelo-suppressive cytokines such as TGF-β, TNF-α and Interferons in MDS hematopoietic stem cells. Targeting these signaling cascades could be potentially therapeutic in MDS. The p38 MAP kinase pathway, which is constitutively activated in MDS, is an example of cytokine stimulated kinase that promotes aberrant apoptosis of stem and progenitor cells in MDS. ARRY-614 and SCIO-469 are p38 MAPK inhibitors that have been used in clinical trials and have shown activity in a subset of MDS patients. TGF-β signaling has been therapeutically targeted by small molecule inhibitor of the TGF-β receptor kinase, LY-2157299, with encouraging preclinical results. Apart from TGF-β receptor kinase inhibition, members of TGF-β super family and BMP ligands have also been targeted by ligand trap compounds like Sotatercept (ACE-011) and ACE-536. The multikinase inhibitor, ON-01910.Na (Rigosertib) has demonstrated early signs of efficacy in reducing the percentage of leukemic blasts and is in advanced stages of clinical testing. Temsirolimus, Deforolimus and other mTOR inhibitors are being tested in clinical trials and have shown preclinical efficacy in CMML. EGF receptor inhibitors, Erlotinib and Gefitinib have shown efficacy in small trials that may be related to off target effects. Cell cycle regulator inhibitors such as Farnesyl transferase inhibitors (Tipifarnib, Lonafarnib) and MEK inhibitor (GSK1120212) have shown acceptable toxicity profiles in small studies and efforts are underway to select mutational subgroups of MDS and AML that may benefit from these inhibitors. Altogether, these studies show that targeting various signal transduction pathways that regulate hematopoiesis offers promising therapeutic potential in this disease. Future studies in combination with high resolution correlative studies will clarify the subgroup specific efficacies of these agents.
Topics: Animals; Antineoplastic Agents; Cytokines; Enzyme Inhibitors; Humans; Myelodysplastic Syndromes; Signal Transduction
PubMed: 23841999
DOI: 10.1186/1756-8722-6-50