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A myelodysplastic syndrome (MDS) is one of a group of cancers in which immature blood cells in the bone marrow do not mature, and as a result, do not develop into healthy blood cells. Early on, no symptoms typically are seen. Later, symptoms may include fatigue, shortness of breath, bleeding disorders, anemia, or frequent infections. Some types may develop into acute myeloid leukemia.
Fanconi anemia (FA) is a rare, autosomal recessive, genetic disease resulting in impaired response to DNA damage in the FA/BRCA pathway. Although it is a very rare disorder, study of this and other bone marrow failure syndromes has improved scientific understanding of the mechanisms of normal bone marrow function and development of cancer. Among those affected, the majority develop cancer, most often acute myelogenous leukemia (AML), MDS, and liver tumors. 90% develop aplastic anemia by age 40. About 60–75% have congenital defects, commonly short stature, abnormalities of the skin, arms, head, eyes, kidneys, and ears, and developmental disabilities. Around 75% have some form of endocrine problem, with varying degrees of severity. 60% of FA is FANC-A, 16q24.3, which has later onset bone marrow failure.
A glioma is a type of primary tumor that starts in the glial cells of the brain or spinal cord. They are cancerous but some are extremely slow to develop. Gliomas comprise about 30 percent of all brain tumors and central nervous system tumours, and 80 percent of all malignant brain tumours.
Glioblastoma, previously known as glioblastoma multiforme (GBM), is the most aggressive and most common type of cancer that originates in the brain, and has a very poor prognosis for survival. Initial signs and symptoms of glioblastoma are nonspecific. They may include headaches, personality changes, nausea, and symptoms similar to those of a stroke. Symptoms often worsen rapidly and may progress to unconsciousness.
Lenalidomide, sold under the brand name Revlimid among others, is a medication used to treat multiple myeloma, smoldering myeloma, and myelodysplastic syndromes (MDS). For multiple myeloma, it is a first line treatment, and is given with dexamethasone. It is taken by mouth.
Fas ligand is a type-II transmembrane protein expressed on various types of cells, including cytotoxic T lymphocytes, monocytes, neutrophils, breast epithelial cells, vascular endothelial cells and natural killer (NK) cells. It binds with its receptor, called FAS receptor and plays a crucial role in the regulation of the immune system and in induction of apoptosis, a programmed cell death.
Azacitidine, sold under the brand name Vidaza among others, is a medication used for the treatment of myelodysplastic syndrome, myeloid leukemia, and juvenile myelomonocytic leukemia. It is a chemical analog of cytidine, a nucleoside in DNA and RNA. Azacitidine and its deoxy derivative, decitabine were first synthesized in Czechoslovakia as potential chemotherapeutic agents for cancer.
A blastoma is a type of cancer, more common in children, that is caused by malignancies in precursor cells, often called blasts. Examples are nephroblastoma, medulloblastoma, and retinoblastoma. The suffix -blastoma is used to imply a tumor of primitive, incompletely differentiated cells, e.g., chondroblastoma is composed of cells resembling the precursor of chondrocytes.
Vorinostat (rINN), also known as suberoylanilide hydroxamic acid, is a member of a larger class of compounds that inhibit histone deacetylases (HDAC). Histone deacetylase inhibitors (HDI) have a broad spectrum of epigenetic activities.
The death-inducing signaling complex or DISC is a multi-protein complex formed by members of the death receptor family of apoptosis-inducing cellular receptors. A typical example is FasR, which forms the DISC upon trimerization as a result of its ligand (FasL) binding. The DISC is composed of the death receptor, FADD, and caspase 8. It transduces a downstream signal cascade resulting in apoptosis.
PAC-1 is a synthesized chemical compound that selectively induces apoptosis, in cancerous cells. It was granted orphan drug status by the FDA in 2016.
The ASAH1 gene encodes in humans the acid ceramidase enzyme.
Epithelial membrane protein 3 (EMP3) is a trans-membrane signaling molecule that is encoded by the myelin-related gene EMP3. EMP3 is a member of the peripheral myelin protein gene family 22-kDa (PMP22), which is mainly responsible for the formation of the sheath of compact myelin. Although the detailed functions and mechanisms of EMP3 still remain unclear, it is suggested that EMP3 is possibly epigenetically linked to certain carcinomas.
BCL2-like 13 , also known as BCL2L13 or Bcl-rambo, is a protein which in humans is encoded by the BCL2L13 gene on chromosome 22. This gene encodes a mitochondrially-localized protein which is classified under the Bcl-2 protein family. Overexpression of the encoded protein results in apoptosis. As a result, it has been implicated in cancers such as childhood acute lymphoblastic leukemia (ALL) and glioblastoma multiforme (GBM). Alternatively spliced transcript variants have been observed for this gene, such as Bcl-rambo beta.
Demethylating agents are chemical substances that can inhibit methylation, resulting in the expression of the previously hypermethylated silenced genes. Cytidine analogs such as 5-azacytidine (azacitidine) and 5-azadeoxycytidine (decitabine) are the most commonly used demethylating agents. They work by inhibiting DNA methyltransferases. Both compounds have been approved in the treatment of myelodysplastic syndrome (MDS) by Food and Drug Administration (FDA) in United States. Azacitidine and decitabine are marketed as Vidaza and Dacogen respectively. Azacitidine is the first drug to be approved by FDA for treating MDS and has been given orphan drug status. Procaine is a DNA-demethylating agent with growth-inhibitory effects in human cancer cells. There are many other demethylating agents that can be used to inhibit the growth of other diseases.
Crenolanib besylate is an investigational inhibitor being developed by AROG Pharmaceuticals, LLC. The compound is currently being evaluated for safety and efficacy in clinical trials for various types of cancer, including acute myeloid leukemia (AML), gastrointestinal stromal tumor (GIST), and glioma. Crenolanib is an orally bioavailable benzimidazole that selectively and potently inhibits signaling of wild-type and mutant isoforms of class III receptor tyrosine kinases (RTK) FLT3, PDGFR α, and PDGFR β. Unlike most RTK inhibitors, crenolanib is a type I mutant-specific inhibitor that preferentially binds to phosphorylated active kinases with the ‘DFG in’ conformation motif.
Temozolomide, sold under the brand name Temodar among others, is an anticancer medication used to treat brain tumors such as glioblastoma and anaplastic astrocytoma. It is taken by mouth or via intravenous infusion.
Alternating electric field therapy, sometimes called tumor treating fields (TTFields), is a type of electromagnetic field therapy using low-intensity, intermediate frequency electrical fields to treat cancer. TTFields disrupt cell division by disrupting dipole alignment and inducing dielectrophoresis of critical molecules and organelles during mitosis. These anti-mitotic effects lead to cell death, slowing cancer growth. A TTField-treatment device manufactured by the Israeli company Novocure is approved in the United States and Europe for the treatment of newly diagnosed and recurrent glioblastoma, malignant pleural mesothelioma (MPM), and is undergoing clinical trials for several other tumor types. Despite earning regulatory approval, the efficacy of this technology remains controversial among medical experts.
Patient derived xenografts (PDX) are models of cancer where the tissue or cells from a patient's tumor are implanted into an immunodeficient or humanized mouse. It is a form of xenotransplantation. PDX models are used to create an environment that allows for the continued growth of cancer after its removal from a patient. In this way, tumor growth can be monitored in the laboratory, including in response to potential therapeutic options. Cohorts of PDX models can be used to determine the therapeutic efficiency of a therapy against particular types of cancer, or a PDX model from a specific patient can be tested against a range of therapies in a 'personalized oncology' approach.
Epitopoietic Research Corporation (ERC) is a Belgian Pharmaceutical company that is specialized in the development of ERC1671, a treatment for Glioblastoma multiforme, which is the most aggressive form of brain cancer. In 2019 ERC provided treatment under the US Federal Right-to-try law.
References
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- ↑ "Orphan designation, Europe". Orphanet, the portal for rare diseases and orphan drugs. 2017-10-05.
- ↑ "Treatment of glioblastoma multiforme". U.S. Food and Drug Administration (FDA). 2012-07-24.
- ↑ "Treatment of Myelodysplastic Syndrome". U.S. Food and Drug Administration (FDA). 2009-10-13.
- ↑ "Asunercep, PRIME Designation" (PDF). European Medicines Agency (EMA). 2017-05-27.
- ↑ Zhu J, Petit PF, Van den Eynde BJ (2018). "Apoptosis of tumor-infiltrating T lymphocytes: a new immune checkpoint mechanism". Cancer Immunol Immunother. 68 (5): 835–847. Bibcode:2017NatCo...8.1404Z. doi: 10.1038/s41467-017-00784-1 . PMC 5680273 . PMID 30406374.
- ↑ Zhu J, Powis de Tenbossche CG, Cané S, Colau D, van Baren N, Lurquin C, Schmitt-Verhulst AM, Liljeström P, Uyttenhove C, Van den Eynde BJ (2017). "Resistance to cancer immunotherapy mediated by apoptosis of tumor-infiltrating lymphocytes". Nat Commun. 8 (1): 1404. Bibcode:2017NatCo...8.1404Z. doi:10.1038/s41467-017-00784-1. PMC 5680273 . PMID 29123081.
- ↑ Motz GT, Santoro SP, Wang LP, Garrabrant T, Lastra RR, Hagemann IS, Lal P, Feldman MD, Benencia F, Coukos G (2014). "Tumor endothelium FasL establishes a selective immune barrier promoting tolerance in tumors". Nat Med. 20 (6): 607–15. doi:10.1038/nm.3541. PMC 4060245 . PMID 24793239.
- ↑ Lakins MA, Ghorani E, Munir H, Martins CP, Shields JD (2018). "Cancer-associated fibroblasts induce antigen-specific deletion of CD8+ T Cells to protect tumour cells". Nat Commun. 9 (1): 948. Bibcode:2018NatCo...9..948L. doi:10.1038/s41467-018-03347-0. PMC 5838096 . PMID 29507342.
- ↑ Raimbault A, Pierre-Eugene C, Rouquette A, Deudon C, Willems L, Chapuis N, Mathis S, Kunz C, Fricke H, Kosmider O, Bardet V, Fontenay M, Groupe Francophone des Myélodysplasies (2016). "APG101 efficiently rescues erythropoiesis in lower risk myelodysplastic syndromes with severe impairment of hematopoiesis". Oncotarget. 22 (12): 14898–911. doi:10.18632/oncotarget.7469. PMC 4924760 . PMID 26910909.
- ↑ Tuettenberg J, Seiz M, Debatin KM, Hollburg W, von Staden M, Thiemann M, Hareng B, Fricke H, Kunz C (2012). "Pharmacokinetics, pharmacodynamics, safety and tolerability of APG101, a CD95-Fc fusion protein, in healthy volunteers and two glioma patients". Int Immunopharmacol. 13 (1): 93–100. doi: 10.1016/j.intimp.2012.03.004 . PMID 22446296.
- ↑ Wick W, Fricke H, Junge K, Kobyakov G, Martens T, Heese O, Wiestler B, Schliesser MG, von Deimling A, Pichler J, Vetlova E, Harting I, Debus J, Hartmann C, Kunz C, Platten M, Bendszus M, Combs SE (2014). "A phase II, randomized, study of weekly APG101+reirradiation versus reirradiation in progressive glioblastoma". Clin Cancer Res. 15 (24): 6304–13. doi: 10.1158/1078-0432.CCR-14-0951-T . PMID 25338498.
- ↑ Boch T, Luft T, Metzgeroth G, Mossner M, Jann JC, Nowak D, Meir F, Schumann C, Klemmer J, Brendel S, Fricke H, Kunz C, Weiß C, Hofmann WK, Nolte F (2018). "Safety and efficacy of the CD95-ligand inhibitor asunercept in transfusion-dependent patients with low and intermediate risk MDS". Leuk Res. 68: 62–69. doi:10.1016/j.leukres.2018.03.007. PMID 29549809.
- ↑ "Myelodysplastic Syndromes Treatment (PDQ®)–Patient Version". National Cancer Institute. 18 February 2005.