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1.
Mol Cancer Ther ; 15(4): 533-47, 2016 04.
Article in English | MEDLINE | ID: mdl-27009213

ABSTRACT

The diagnosis, classification, and management of cancer are traditionally dictated by the site of tumor origin, for example, breast or lung, and by specific histologic subtypes of site-of-origin cancers (e.g., non-small cell versus small cell lung cancer). However, with the advent of sequencing technologies allowing for rapid, low cost, and accurate sequencing of clinical samples, new observations suggest an expanded or different approach to the diagnosis and treatment of cancer-one driven by the unique molecular features of the tumor. We discuss a genomically driven strategy for cancer treatment using BRAF as an example. Several key points are highlighted: (i) molecular aberrations can be shared across cancers; (ii) approximately 15% of all cancers harbor BRAF mutations; and (iii) BRAF inhibitors, while approved only for melanoma, have reported activity across numerous cancers and related disease types bearing BRAF aberrations. However, BRAF-mutated colorectal cancer has shown poor response rate to BRAF inhibitor monotherapy, striking a cautionary note. Yet, even in this case, emerging data suggest BRAF-mutated colorectal cancers can respond well to BRAF inhibitors, albeit when administered in combination with other agents that impact resistance pathways. Taken together, these data suggest that molecular aberrations may be the basis for a new nosology for cancer. Mol Cancer Ther; 15(4); 533-47. ©2016 AACR.


Subject(s)
Genetic Association Studies , Genetic Predisposition to Disease , Genetic Variation , Neoplasms/diagnosis , Neoplasms/genetics , Animals , Antineoplastic Agents/pharmacology , Antineoplastic Agents/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Genetic Testing/methods , Humans , MAP Kinase Signaling System/drug effects , Molecular Targeted Therapy , Mutation , Neoplasms/drug therapy , Prognosis , Protein Kinase Inhibitors/pharmacology , Protein Kinase Inhibitors/therapeutic use , Proto-Oncogene Proteins B-raf/antagonists & inhibitors , Proto-Oncogene Proteins B-raf/genetics , Proto-Oncogene Proteins B-raf/metabolism , Treatment Outcome
2.
Discov Med ; 19(103): 101-8, 2015 Feb.
Article in English | MEDLINE | ID: mdl-25725224

ABSTRACT

With the advent of genomics-based treatment in recent years, the use of targeted therapies in the treatment of various malignancies has increased exponentially. Though much data is available regarding the efficacy of targeted therapies for common malignancies, genetic cancer syndromes remain a somewhat unexplored topic with comparatively less published literature. This review seeks to characterize targeted therapy options for the following genetic cancer syndromes: Fanconi anemia, inherited medullary thyroid cancer, tuberous sclerosis, and RASopathies. By understanding the pathophysiology of these conditions as well as available molecularly targeted therapies, oncologists, in collaboration with geneticists and genetic counsellors, can begin to develop effective clinical management options and therapy regimens for the patients with these genetic syndromes that they may encounter in their practice.


Subject(s)
Fanconi Anemia/genetics , Fanconi Anemia/therapy , Molecular Targeted Therapy , Thyroid Neoplasms/therapy , Tuberous Sclerosis/therapy , ras Proteins/metabolism , Carcinoma, Neuroendocrine , Humans , Syndrome , Thyroid Neoplasms/genetics , Tuberous Sclerosis/genetics
3.
Discov Med ; 19(103): 109-16, 2015 Feb.
Article in English | MEDLINE | ID: mdl-25725225

ABSTRACT

Von Hippel-Lindau disease, Cowden syndrome, and Proteus syndrome are cancer syndromes which affect multiple organs and lead to significant decline in quality of life in affected patients. These syndromes are rare and typically affect the adolescent and young adult population, resulting in greater cumulative years of life lost. Improved understanding of the underpinnings of the genetic pathways underlying these syndromes and the rapid evolution of targeted therapies in general have made it possible to develop therapeutic options for these patients and other genetic cancer syndromes. Targeted therapies especially antiangiogenics and inhibitors of the PIK3CA/AKT/mTOR signaling pathway have shown activity in selected group of patients affected by these syndromes or in patients harboring specific sporadic mutations which are otherwise characteristic of these syndromes. Unfortunately due to the rare nature, patients with these syndromes are not the focus of clinical trials and unique results seen in these patients can easily go unnoticed. Most of the data suggesting benefits of targeted therapies are either case reports or small case series. Thus, a literature review was indicated. In this review we explore the use of molecularly targeted therapy options in Von Hippel-Lindau disease, Cowden syndrome, and Proteus syndrome.


Subject(s)
Hamartoma Syndrome, Multiple/therapy , Molecular Targeted Therapy , Neoplasms/genetics , Neoplasms/therapy , Proteus Syndrome/therapy , von Hippel-Lindau Disease/therapy , Humans , Syndrome
4.
Oncoscience ; 1(10): 614-623, 2014.
Article in English | MEDLINE | ID: mdl-25593991

ABSTRACT

The increasing scope and availability of genetic testing options for patients suffering from cancer has raised questions about how to use results of molecular diagnostics to inform patient care. For some biomarkers (e.g. BRAF mutations in melanoma), standards exist that outline treatments for individuals harboring aberrations in the biomarker; however for the vast majority of genomic abnormalities, few guidelines exist. Clinical decision making and the therapeutic approach for a patient with a given cancer characterized by aberrations in different genes may be aided by the use of a biomarker actionability framework that provides levels of evidence regarding whether and how a molecular abnormality can be considered a therapeutically relevant biomarker. A gene may be considered theoretically actionable if it has a basis of actionability, such that clinically available drugs can target a gene product that drives the cancer or is differentially expressed in tumor versus normal elements. Herein, we discuss a possible framework for developing guidelines for actionability, as they relate to genomically-based cancer therapeutics.

5.
Discov Med ; 18(101): 323-30, 2014 Dec.
Article in English | MEDLINE | ID: mdl-25549703

ABSTRACT

Hereditary cancer syndromes are well known in the oncology community, typically affecting children, adolescents, and young adults and thereby resulting in great cumulative morbidity and mortality. These syndromes often lag behind their de novo counterparts in the development of approved novel treatment options due to their rarity in the general population. Recent work has allowed the identification of molecular aberrations and associated targeted therapies that may effectively treat these conditions. In this review, we seek to characterize some of the involved aberrations and associated targeted therapies for several germline malignancies, including neurofibromatosis types 1 and 2, and Gorlin syndrome. Though patients with hereditary cancer syndromes may be too rare to effectively include in large clinical trials, by understanding the pathophysiology of these diseases, clinicians can attain insights into the use of targeted therapies in their own practice when treating affected individuals.


Subject(s)
Basal Cell Nevus Syndrome/drug therapy , Neurofibromatosis 1/drug therapy , Neurofibromatosis 2/drug therapy , Antineoplastic Agents/therapeutic use , Basal Cell Nevus Syndrome/genetics , Humans , Neurofibromatosis 1/genetics , Neurofibromatosis 2/genetics
6.
Discov Med ; 18(101): 331-9, 2014 Dec.
Article in English | MEDLINE | ID: mdl-25549704

ABSTRACT

Cancer genetics has rapidly evolved in the last two decades. Understanding and exploring the several genetic pathways in the cancer cell is the foundation of targeted therapy. Several genomic aberrations have been identified and their role in carcinogenesis is being explored. In contrast to most cancers where these mutations are acquired, patients with hereditary cancer syndromes have inherited genomic aberrations. The understanding of the molecular pathobiology in hereditary cancer syndromes has advanced dramatically. In addition, many molecularly targeted therapies have been developed that could have potential roles in the treatment of patients with hereditary cancer syndromes. In this review, we outline the presentation, molecular biology, and possible targeted therapies for two of the most widely recognized hereditary cancer syndromes -- hereditary breast and ovarian cancer syndrome and hereditary non-polyposis colorectal cancer syndrome (Lynch syndrome). We will also discuss other syndromes such as familial adenomatous polyposis and Li-Fraumeni syndrome (TP53).


Subject(s)
Adenomatous Polyposis Coli/drug therapy , Antineoplastic Agents/therapeutic use , Colorectal Neoplasms, Hereditary Nonpolyposis/drug therapy , Hereditary Breast and Ovarian Cancer Syndrome/drug therapy , Li-Fraumeni Syndrome/drug therapy , Adenomatous Polyposis Coli/genetics , Colorectal Neoplasms, Hereditary Nonpolyposis/genetics , Hereditary Breast and Ovarian Cancer Syndrome/genetics , Humans , Li-Fraumeni Syndrome/genetics , Mutation
7.
PLoS One ; 7(2): e31906, 2012.
Article in English | MEDLINE | ID: mdl-22363766

ABSTRACT

The remarkably heterogeneous nature of lung cancer has become more apparent over the last decade. In general, advanced lung cancer is an aggressive malignancy with a poor prognosis. The discovery of multiple molecular mechanisms underlying the development, progression, and prognosis of lung cancer, however, has created new opportunities for targeted therapy and improved outcome. In this paper, we define "molecular subtypes" of lung cancer based on specific actionable genetic aberrations. Each subtype is associated with molecular tests that define the subtype and drugs that may potentially treat it. We hope this paper will be a useful guide to clinicians and researchers alike by assisting in therapy decision making and acting as a platform for further study. In this new era of cancer treatment, the 'one-size-fits-all' paradigm is being forcibly pushed aside-allowing for more effective, personalized oncologic care to emerge.


Subject(s)
Lung Neoplasms/classification , Lung Neoplasms/genetics , Molecular Typing , Antineoplastic Agents/pharmacology , Antineoplastic Agents/therapeutic use , Cell Death/drug effects , Cell Proliferation/drug effects , ErbB Receptors/metabolism , Humans , Lung Neoplasms/drug therapy , Lung Neoplasms/pathology , Phosphatidylinositol 3-Kinases/metabolism , Proto-Oncogene Proteins c-akt/metabolism , Signal Transduction/drug effects
8.
PLoS One ; 6(3): e18257, 2011 Mar 30.
Article in English | MEDLINE | ID: mdl-21479172

ABSTRACT

While advanced melanoma remains one of the most challenging cancers, recent developments in our understanding of the molecular drivers of this disease have uncovered exciting opportunities to guide personalized therapeutic decisions. Genetic analyses of melanoma have uncovered several key molecular pathways that are involved in disease onset and progression, as well as prognosis. These advances now make it possible to create a "Molecular Disease Model" (MDM) for melanoma that classifies individual tumors into molecular subtypes (in contrast to traditional histological subtypes), with proposed treatment guidelines for each subtype including specific assays, drugs, and clinical trials. This paper describes such a Melanoma Molecular Disease Model reflecting the latest scientific, clinical, and technological advances.


Subject(s)
Melanoma/genetics , Models, Biological , Humans , Melanoma/classification , Melanoma/therapy , Molecular Targeted Therapy , Signal Transduction/genetics , Treatment Outcome
9.
J Cell Sci ; 116(Pt 1): 137-43, 2003 Jan 01.
Article in English | MEDLINE | ID: mdl-12456723

ABSTRACT

The centriole, organizer of the centrosome, duplicates by assembling a unique daughter identical to itself in overall organization and length. The centriole is a cylindrical structure composed of nine sets of microtubules and is thus predicted to have nine-fold symmetry. During duplication, a daughter lacking discrete microtubular organization first appears off the wall of the mother centriole. It increases in length perpendicularly away from the mother and terminates growth when it matches the length of the mother. How a unique daughter of the correct length and overall organization is assembled is unknown. Here, we describe three types of unusual centriole configurations observed in wing imaginal discs of Drosophila following inactivation of Cdk1. First, we observed centriole triplets consisting of one mother and two daughters, which suggested that centrioles have more than one potential site for the assembly of daughters. Second, we observed centriole triplets comprising a grandmother, mother and daughter, which suggested that subsequent centriole duplication cycles do not require separation of mother and daughter centrioles. Finally, we observed centriole pairs in which the daughter is longer than its mother. These findings suggest that regulatory events rather than rigid structural constraints dictate features of the stereotyped duplication program of centrioles.


Subject(s)
CDC2 Protein Kinase/deficiency , Cell Division/genetics , Centrioles/pathology , Drosophila melanogaster/growth & development , Larva/growth & development , Wings, Animal/growth & development , Animals , CDC2 Protein Kinase/genetics , Cell Cycle Proteins/genetics , Centrioles/genetics , Centrioles/ultrastructure , Drosophila melanogaster/cytology , Drosophila melanogaster/genetics , Gene Expression Regulation, Developmental/genetics , Genes, cdc/physiology , Larva/cytology , Larva/genetics , Microscopy, Electron , Microtubules/genetics , Microtubules/metabolism , Microtubules/ultrastructure , Wings, Animal/cytology , Wings, Animal/metabolism
10.
Curr Biol ; 12(10): 829-33, 2002 May 14.
Article in English | MEDLINE | ID: mdl-12015119

ABSTRACT

When mitosis is bypassed, as in some cancer cells or in natural endocycles, sister chromosomes remain paired and produce four-stranded diplochromosomes or polytene chromosomes. Cyclin/Cdk1 inactivation blocks entry into mitosis and can reset G2 cells to G1, allowing another round of replication. Reciprocally, persistent expression of Cyclin A/Cdk1 or Cyclin E/Cdk2 blocks Drosophila endocycles. Inactivation of Cyclin A/Cdk1 by mutation or overexpression of the Cyclin/Cdk1 inhibitor, Roughex (Rux), converts the 16(th) embryonic mitotic cycle to an endocycle; however, we show that Rux expression fails to convert earlier cell cycles unless Cyclin E is also downregulated. Following induction of a Rux transgene in Cyclin E mutant embryos during G2 of cell cycle 14 (G2(14)), Cyclins A, B, and B3 disappeared and cells reentered S phase. This rereplication produced diplochromosomes that segregated abnormally at a subsequent mitosis. Thus, like the yeast CKIs Rum1 and Sic1, Drosophila Rux can reset G2 cells to G1. The observed cyclin destruction suggests that cell cycle resetting by Rux was associated with activation of the anaphase-promoting complex (APC), while the presence of diplochromosomes implies that this activation of APC outside of mitosis was not sufficient to trigger sister disjunction.


Subject(s)
Chromatids/metabolism , Chromosome Segregation , DNA Replication , Drosophila Proteins , Drosophila/cytology , Drosophila/embryology , Animals , Cell Cycle , Chromatids/genetics , Cyclin A/metabolism , Cyclin B/metabolism , Cyclin E/genetics , Cyclin E/metabolism , Down-Regulation , Drosophila/genetics , Eye Proteins/metabolism , In Situ Hybridization, Fluorescence , Mitosis , Mutation
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