scholarly journals Fusion Oncoproteins in Childhood Cancers: Potential Role in Targeted Therapy

2021 ◽  
Vol 26 (6) ◽  
pp. 541-555
Author(s):  
Sara D. A. Angione ◽  
Alemayehu Y. Akalu ◽  
Jessica Gartrell ◽  
Elimika Pfuma Fletcher ◽  
Gilbert J. Burckart ◽  
...  
Keyword(s):  
Targeted Therapy ◽  
Molecular Genetics ◽  
Cause Of Death ◽  
Scientific Knowledge ◽  
Targeted Therapies ◽  
Potential Role ◽  
Chromosomal Rearrangements ◽  
Childhood Cancers ◽  
Pediatric Cancers ◽  
Pediatric Sarcomas

Cancer remains the leading cause of death from disease in children. Historically, in contrast to their adult counterparts, the causes of pediatric malignancies have remained largely unknown, with most pediatric cancers displaying low mutational burdens. Research related to molecular genetics in pediatric cancers is advancing our understanding of potential drivers of tumorigenesis and opening new opportunities for targeted therapies. One such area is fusion oncoproteins, which are a product of chromosomal rearrangements resulting in the fusion of different genes. They have been identified as oncogenic drivers in several sarcomas and leukemias. Continued advancement in the understanding of the biology of fusion oncoproteins will contribute to the discovery and development of new therapies for childhood cancers. Here we review the current scientific knowledge on fusion oncoproteins, focusing on pediatric sarcomas and hematologic cancers, and highlight the challenges and current efforts in developing drugs to target fusion oncoproteins.

scholarly journals A potential role for targeted therapy in a subset of metastasizing adnexal carcinomas

2011 ◽  
Vol 24 (7) ◽  
pp. 974-982 ◽  
Author(s):  
Dora Dias-Santagata ◽  
Quynh Lam ◽  
Kristin Bergethon ◽  
Gabrielle M Baker ◽  
A John Iafrate ◽  
...  
Keyword(s):  
Targeted Therapy ◽  
Potential Role

Targeted Therapy and Molecular Genetics

2018 ◽  
pp. 470-492.e10 ◽  
Author(s):  
Shannon N. Westin ◽  
Anil K. Sood ◽  
Robert L. Coleman
Keyword(s):  
Targeted Therapy ◽  
Molecular Genetics

scholarly journals Beyond KRAS: Practical Molecular Targets in Pancreatic Adenocarcinoma

2019 ◽  
Vol 12 (1) ◽  
pp. 7-13 ◽  
Author(s):  
Albert Grinshpun ◽  
Yonaton Zarbiv ◽  
Jason Roszik ◽  
Vivek Subbiah ◽  
Ayala Hubert
Keyword(s):  
Clinical Trials ◽  
Targeted Therapy ◽  
Pancreatic Adenocarcinoma ◽  
Targeted Therapies ◽  
Kras Mutation ◽  
Molecular Targets ◽  
Driver Mutations ◽  
Proof Of Concept ◽  
Genomic Analyses ◽  
Variable Success

Pancreatic adenocarcinoma (PDAC) has a grim prognosis. Molecular and genomic analyses revealed that the striking majority of these tumors are driven by KRAS mutation, currently not amenable to targeted therapy. However, other driver mutations were found in a small fraction of patients. Herein we report of 3 cases of patients with metastatic PDAC and wildtype KRAS, found to harbor BRAF or RET pathogenic alterations. The patients were treated with targeted therapies with variable success. In our opinion, those proof-of-concept cases argue in favor of additional research and clinical trials’ effort in this small but significant PDAC population with uncommon driver mutations.

scholarly journals Targeted therapy in pulmonary veno-occlusive disease: time for a rethink?

2019 ◽  
Vol 19 (1) ◽  
Author(s):  
Qin Luo ◽  
Qi Jin ◽  
Zhihui Zhao ◽  
Qing Zhao ◽  
Xue Yu ◽  
...  
Keyword(s):  
Targeted Therapy ◽  
Pulmonary Edema ◽  
Exercise Capacity ◽  
Targeted Therapies ◽  
Occlusive Disease ◽  
Heart Catheterization ◽  
Long Term Outcome ◽  
Pulmonary Arterial

Abstract Background Pulmonary veno-occlusive disease (PVOD) is a rare condition with poor prognosis, and lung transplantation is recommended as the only curative therapy. The role of pulmonary arterial hypertension targeted therapy in PVOD remains controversial, and long-term effects of targeted therapy have been rarely reported. This study aims to retrospectively evaluate the role of targeted therapy in PVOD patients and the long-term outcome. Methods PVOD patients with good responses to targeted therapies were analyzed, and data pre- and post- targeted therapies were compared. An overview of the effects of targeted therapies on PVOD patients was also conducted. Results Five genetically or histologically confirmed PVOD patients received targeted therapies and showed good responses. Their mean pulmonary arterial pressure by right heart catheterization was 62.0 ± 11.7 mmHg. Two receiving monotherapy got stabilized, and three receiving sequential combination therapy got improved, cardiac function and exercise capacity significantly improved after treatments. No pulmonary edema occurred. The mean time from the first targeted therapy to the last follow up was 39.3 months, and the longest was 9 years. A systematic review regarding the effects of targeted therapies on PVOD patients indicated majorities of patients got hemodynamics or 6-min walk distance improved, and 26.7% patients developed pulmonary edema. The interval from targeted drugs use to death ranged from 71 min to over 4 years. Conclusions Cautious use of targeted therapy could safely and effectively improve or stabilize hemodynamics and exercise capacity of some patients without any complications. PVOD patients could live longer than expected.

scholarly journals Personalized Medicine in the Oncology Clinic: Implementation and Outcomes of the Johns Hopkins Molecular Tumor Board

2017 ◽  
pp. 1-19 ◽  
Author(s):  
W. Brian Dalton ◽  
Patrick M. Forde ◽  
Hyunseok Kang ◽  
Roisin M. Connolly ◽  
Vered Stearns ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Targeted Therapy ◽  
Targeted Therapies ◽  
Progression Free Survival ◽  
Molecular Profiling ◽  
Tumor Board ◽  
Free Survival ◽  
Off Label ◽  
Tumor Boards ◽  
Molecular Tumor Board

Purpose Tumor genomic profiling for personalized oncology therapy is being widely applied in clinical practice even as it is being evaluated more formally in clinical trials. Given the complexities of genomic data and its application to clinical use, molecular tumor boards with diverse expertise can provide guidance to oncologists and patients seeking to implement personalized genetically targeted therapy in practice. Methods A multidisciplinary molecular tumor board reviewed tumor molecular profiling reports from consecutive referrals at the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins over a 3-year period. The tumor board weighed evidence for actionability of genomic alterations identified by molecular profiling and provided recommendations including US Food and Drug Administration–approved drug therapy, clinical trials of matched targeted therapy, off-label use of such therapy, and additional tumor or germline genetic testing. Results One hundred fifty-five patients were reviewed. Actionable genomic alterations were identified in 132 patients (85%). Off-label therapies were recommended in 37 patients (24%). Eleven patients were treated off-label, and 13 patients were enrolled onto clinical trials of matched targeted therapies. Median progression-free survival of patients treated with matched therapies was 5 months ( 95% CI, 2.9 months to not reached), and the progression-free survival probability at 6 months was 43% (95% CI, 26% to 71%). Lack of locally available clinical trials was the major limitation on clinical actionability of tumor profiling reports. Conclusion The molecular tumor board recommended off-label targeted therapies for a quarter of all patients reviewed. Outcomes were heterogeneous, although 43% of patients receiving genomically matched therapy derived clinical benefit lasting at least 6 months. Until more data become available from precision oncology trials, molecular tumor boards can help guide appropriate use of tumor molecular testing to direct therapy.

Patients with Acute Myelogenous Leukemia (AML) or High-Risk Myelodysplastic Syndrome (HR-MDS) Treated with Targeted Therapy May Benefit from Prophylactic Measures Against Infections.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 4483-4483 ◽  
Author(s):  
Gloria N. Mattiuzzi ◽  
Jorge E. Cortes ◽  
Stefan Faderl ◽  
Maria E. Cabanillas ◽  
Francis J. Giles ◽  
...  
Keyword(s):  
Targeted Therapy ◽  
Supportive Care ◽  
Cause Of Death ◽  
Performance Status ◽  
Unknown Origin ◽  
Infectious Complications ◽  
Myelogenous Leukemia ◽  
High Dose ◽  
Overall Response ◽  
Prophylactic Measures

Abstract Targeted therapy (TT) has emerged as an alternative for patients (pts) 60 years or older with hematologic malignancies. It has been suggested that these approaches produce fewer and less severe side effects than conventional chemotherapy (CC) and could potentially decrease mortality. In the current study, pts with AML or HR-MDS treated with TT and CC were compared with regard to infectious complications and induction mortality. Supportive care measures for pts on CC were given according to our departmental guidelines (protective environment (PE) was offered and antibacterial, antifungal and antiviral prophylaxis were given from D1 to ANC ≥ 500). Pts on TT were given supportive care measures according to protocol requirements. HR-MDS pts: 29 pts were treated with TT and 13 with CC. Pts on TT were significantly older than those on CC (median age: 66(r: 46–85) and 59(r: 17–73) respectively, p=0.02). All 42 pts (TT and CC) had Zubrod performance status (PS) ≤ 2. 16/29 (90%) pts on TT received Decitabine; 2 pts received 5-AZA containing regimens and 1 pt received rosiglitazone + targetrin. Nine pts (69%) on CC had high-dose ara-C (HDAC) containing regimens; 1 pt received cloretazine + hydrea and 3 pts had low-dose ara-C (LDAC) + clofarabine. AML pts: 43 pts were treated with TT and 282 received CC. Pts on TT were significantly older than those on CC (median age: 75(r: 39–86) and 62(r: 17–84) respectively, p<0.001). The majority of the pts in TT (91%) and CC (97%) had PS ≤ 2. Decitabine was given to 40% (17/43) of pts on TT, 25% received 5-AZA containing regimens, 35% had others. HDAC containing regimens were given to 60% of pts on CC and clofarabine and/or LDAC to 40%. Table 1 and 2 show outcome and infectious episodes (IE) in pts with MDS and AML, respectively. Conclusions: Although pts with AML or HR-MDS treated with TT develop significantly fewer number of IE compared to pts treated with CC the severity of such infections lead to similar mortality rate than pts treated with CC. Pts treated with TT may benefit from prophylactic measures against infections. Table 1 Outcome in MDS TT (N=29) CC (N=13) 12 aspergillosis, 1 MRSA sepsis; 2p=ns Response, n(%) Overall response 18(62) 8(61) Resistant 8(28) 4(31) Induction death 3(10) 1(8) p=0.787 Cause of Death, n(%) Infections 3(100)1 - Progressive disease - 1(100) Pts on prophylaxis, n(%) Fungal 11(38) 12(92) p=0.001 Bacterial 19(66) 9(69) p=0.810 Pts in PE, n(%) 0 10(77) p<0.001 Pts with IE, n(%) 15(52) 11(85) p=0.042 IE2, n(%) 19 14 Bacterial 5(26) 2(14) FUO 8(42) 9(64) Pneumonia unknown origin 2(11) 3(21) Fungal 2(11) 0 Others 2(11) 0 Table 2 Outcome in AML TT (N=43) CC(N=282) 1TT:sepsis=5, CC:fungal=4, sepsis=16; 2multiorgan failure; 3p=ns Response, n(%) Overall response 12(28) 180(64) Resistant 27(58) 67(24) Induction death 6(14) 35(12) p=0.779 Cause of death, n(%) Infection1 5(83) 20(57) MOF2 1(14) 7(20) Others - 8(23) Pts on prophylaxis, n(%) Fungal 16(37) 260(92) p=0.001 Bacterial 24(56) 282(100) p=0.001 Pts in PE, n(%) 6(14) 214(76) p<0.001 Pts with IE, n(%) 22(51) 247(88) p<0.001 IE3, n(%) 31 405 Bacterial 7(22) 88(22) FUO 13(42) 202(50) Pneumonia unknown origin 6(19) 93(23) Fungal 1(3) 10(2) Virus 2(6) 6(1) Others 2(6) 6(1)

Economic burden of adverse events in patients with metastatic renal cell carcinoma (mRCC).

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. e16573-e16573
Author(s):  
May Hagiwara ◽  
Rohit Borker ◽  
Gerry Oster
Keyword(s):  
Abdominal Pain ◽  
Back Pain ◽  
Targeted Therapy ◽  
Adverse Events ◽  
Targeted Therapies ◽  
Index Date ◽  
Line Treatment ◽  
First Line ◽  
Baseline Characteristics ◽  
First Line Treatment

e16573 Background: To estimate costs associated with adverse events (AEs) in patients receiving targeted therapies indicated for first-line treatment of mRCC. Methods: A retrospective study using a large US healthcare claims database (PharMetrics) from 1/2000 to 12/2009 was conducted. Study subjects were aged ≥18 years, had mRCC, and received first-line treatment with targeted therapies. AEs of interest comprised abdominal pain, back pain, diarrhea, dyspnea, extremity pain, fatigue/asthenia, hand-foot syndrome, hypertension, lymphopenia, nausea/vomiting, neutropenia, and proteinuria. Patients receiving care for these AEs were identified using ICD-9-CM diagnosis/procedure codes on healthcare claims. Costs were examined over a 30-day period, beginning with date of first mention of each AE; non-evented patients were assigned a “shadow” index date for comparison purposes. We estimated total costs over 30 days following the index date for patients with and without AEs, on both unadjusted basis and following adjustment for differences in baseline characteristics using a generalized linear model (GLM). Direct costs of targeted therapy were not considered. Results: Among patients receiving targeted therapy for mRCC, 64% had healthcare encounters for one or more AEs. AEs occurring with frequency >20% included severe abdominal pain, back pain, fatigue/asthenia, and nausea/vomiting, respectively; 10-20% of patients had encounters for diarrhea, dyspnea, and extremity pain, respectively. Mean [SD] total costs of care during the 30-day, post-index period were substantially higher among patients with AEs ($12,177 [$19,621] vs $4070 [$8142] for those without AEs). Adjusting for differences in baseline characteristics, the estimated cost difference (95% CI) was $11,373 ($5286 - $21,419). Conclusions: Costs associated with AEs of first-line targeted therapies are substantial in patients with mRCC. Efforts to prevent and/or better manage these events may reduce healthcare costs.

Matching insurance claims data with EMR molecular status data in non-small cell lung cancer (NSCLC) patients: Understanding real-world molecular testing and prevalence rates at the site and investigator level.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e20568-e20568
Author(s):  
Michael Gregory Cushion ◽  
Bhavani Krishnan ◽  
Jeff Paul Hodge ◽  
Jaya Chandra Balusu ◽  
Joseph Wagner ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Clinical Trials ◽  
Targeted Therapy ◽  
Real World ◽  
Targeted Therapies ◽  
Claims Data ◽  
Molecular Testing ◽  
Insurance Claims ◽  
Insurance Claims Data ◽  
Nsclc Patients

e20568 Background: Many targeted therapy clinical trials require a somatic gene mutation/alteration for eligibility. We assessed the feasibility of leveraging Real-World Data (RWD) to enrol NSCLC patients into clinical trials. Methods: US insurance claims data were extracted to identify lung cancer patients. These data were matched with EMR data also containing NSCLC patients’ details regarding the occurrence and results of molecular testing for EGFR, ALK, ROS1, JAK2, HER2 and RET somatic alterations, achieving a level of granular detail beyond that available in each individual dataset. A one-year extraction period was applied, with no gender or age restrictions. Results: Results for the matched dataset are summarised in the table below - the overall patient record match was 89.6%. Conclusions: The observed prevalence correlated reasonably well with literature reported prevalence for the molecular biomarkers associated commercially available targeted therapies in NSCLC (EGFR, ALK, ROS1). The sample size for the remaining biomarkers was too small to draw conclusions, though the presence of data correlating to these is of interest, considering that there are no currently approved targeted therapies in NSCLC tailored to these predictive biomarkers. This approach could be expanded upon to recruit patients into targeted therapy clinical trials as the dataset is fully linkable to sites and investigators. With the emergence of broad genomic profiling, the availability of molecular data to support clinical trial enrolment is also expected to grow.[Table: see text]

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