Prognosis, Biology, and Targeting of TP53 Dysregulation in Multiple Myeloma

Flynt, Erin; Bisht, Kamlesh; Sridharan, Vinidhra; Ortiz, María; Towfic, Fadi; Thakurta, Anjan

doi:10.3390/cells9020287

Cited by 50 publications

(42 citation statements)

References 153 publications

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“…This correlation is specially known in haematological neoplasms [70] like multiple myeloma, where hemizygous TP53 mutation is associated with increased p53 nuclear expression due to mutations in the remaining allele [71,72]. In this disease, TP53 alterations can occur in three subsets: monoallelic deletion, monoallelic mutations and biallelic inactivation, where monoallelic deletion is the only currently associated with a high risk profile [73].…”

Section: Discussionmentioning

confidence: 93%

TP53 Abnormalities and MMR Preservation in 5 Cases of Proliferating Trichilemmal Tumours

et al. 2021

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Proliferating trichilemmal tumours (PTT) are defined by a benign squamous cell proliferation inside a trichilemmal cystic (TC) cavity. A possible explanation of this proliferative phenomenon within the cyst may be molecular alterations in genes associated to cell proliferation, which can be induced by ultraviolet radiation. Among other genes, alterations on TP53 and DNA mismatch repair proteins (MMR) may be involved in the cellular proliferation observed in PTT. Based on this assumption, but also taking into account the close relationship between the sebaceous ducts and the external root sheath where TC develop, a MMR, a p53 expression assessment and a TP53 study were performed in a series of 5 PTT cases, including a giant one. We failed to demonstrate a MMR disorder on studied PTT, but we agree with previous results suggesting increased p53 expression in these tumours, particularly in proliferative areas. TP53 alteration was confirmed with FISH technique, demonstrating TP53 deletion in most cells.

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Section: Discussionmentioning

confidence: 93%

TP53 Abnormalities and MMR Preservation in 5 Cases of Proliferating Trichilemmal Tumours

et al. 2021

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“…The tumor suppressor P53 is altered in approximately 50% of human cancers ( 62 ). The aberrant TP53 gene, resulted from the deletion or mutation of the TP53 gene (TP53mut), is one of the key biomarkers of poor prognosis of MM ( 63 ).…”

Section: Molecular Signaling Pathways and Transcription Factors Leadimentioning

confidence: 99%

Metabolic Reprogramming Induces Immune Cell Dysfunction in the Tumor Microenvironment of Multiple Myeloma

Kuang

Jin³

et al. 2021

Front. Oncol.

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Tumor cells rewire metabolism to meet their increased nutritional demands, allowing the maintenance of tumor survival, proliferation, and expansion. Enhancement of glycolysis and glutaminolysis is identified in most, if not all cancers, including multiple myeloma (MM), which interacts with a hypoxic, acidic, and nutritionally deficient tumor microenvironment (TME). In this review, we discuss the metabolic changes including generation, depletion or accumulation of metabolites and signaling pathways, as well as their relationship with the TME in MM cells. Moreover, we describe the crosstalk among metabolism, TME, and changing function of immune cells during cancer progression. The overlapping metabolic phenotype between MM and immune cells is discussed. In this sense, targeting metabolism of MM cells is a promising therapeutic approach. We propose that it is important to define the metabolic signatures that may regulate the function of immune cells in TME in order to improve the response to immunotherapy.

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“…Consequently, TP53 is now considered as a suitable target for MM therapy particularly inhibition of MDM2 cascade by nutlin compounds. 129 Idasanutlin is a NDM2 antagonist that activates TP53 , blocks proliferation and induces apoptosis. A Phase I/II study in combination with ixazomib and dexamethasone is ongoing (NCT02633059).…”

Section: “Old” Generation Immunotherapiesmentioning

confidence: 99%

Novel Experimental Drugs for Treatment of Multiple Myeloma

Offidani

Corvatta²,

Morè

et al. 2021

JEP

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Multiple myeloma (MM) is the second most frequent hematological malignancy characterized by bone marrow aberrant plasma cells proliferation leading to a genetic complex and heterogeneous disease, with a median survival ranging from two to more than 10 years. By using new drugs such as proteasome inhibitors (PIs), immunomodulatory drugs (IMiDs), monoclonal antibodies (mAbs) in different combinations and high-dose therapy followed by auto-transplantation, there has been an amazing improvement in the outcome of this disease in recent years. Despite this, MM is still considered an incurable disease, characterized by remission periods alternated with relapse/progression episodes finally leading to resistant disease. In particular, patients who become refractory to PIs, IMiDs and mAbs have a very poor outcome. Moreover, to overcome resistant residual disease, a large combination of drugs will be increasingly used in early lines of therapy; this further reduces the therapeutic options at each relapse. This natural history means that MM always needs new drugs/strategies to overcome the incoming resistance. New combinations of naked mAbs are becoming the therapy of choice for patients refractory to lenalidomide and/or PI; conjugated mAbs will be useful in triple- and more-refractory patients; CAR-T cells and bispecific mAbs have shown relevant results in very advanced stages of disease. In this review, we reported the results of these new therapies and explored their potential applications. Personalized and precision medicine seem to be the new frontier of cancer treatment. Although no single or few factors have been identified as disease drivers in MM, recurrent gene mutations were recognized and specific compounds targeting these alterations were developed and studied. Therefore, we reviewed these targeted drugs to try to understand what the best therapeutic strategy in MM is.

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Prognosis, Biology, and Targeting of TP53 Dysregulation in Multiple Myeloma

Cited by 50 publications

References 153 publications

TP53 Abnormalities and MMR Preservation in 5 Cases of Proliferating Trichilemmal Tumours

TP53 Abnormalities and MMR Preservation in 5 Cases of Proliferating Trichilemmal Tumours

Metabolic Reprogramming Induces Immune Cell Dysfunction in the Tumor Microenvironment of Multiple Myeloma

Novel Experimental Drugs for Treatment of Multiple Myeloma

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