“Direct to Drug” screening as a precision medicine tool in multiple myeloma

Campos, Cecília Bonolo de; Meurice, Nathalie; Petit, Joachim; Polito, Alysia; Zhu, Yuan Xiao; Wang, Panwen; Bruins, Laura A.; Wang, Xuewei; Armenta, Ilsel D Lopez; Darvish, Susie A.; Ahmann, Greg; Henderson, Kimberly J.; Tian, Shulan; Kruse, Jonas; Stewart, William; Larsen, Jeremy T.; Reeder, Craig B.; Dingli, David; Kapoor, Prashant; Kumar, Shaji; Fonseca, Rafaël; Bergsagel, P. Leif; Braggio, Esteban; Stewart, A. Keith

doi:10.1038/s41408-020-0320-7

Cited by 22 publications

(33 citation statements)

References 57 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In light of this, high-throughput drug screenings can accelerate the discovery of synergistic drug combinations. Recently, Bonolo de Campos [53] assembled a standardized MM drug panel and screening platform for drug profiling in 25 MM cell lines, 15 non-Hodgkin's lymphoma cell lines, and in 113 primary MM samples. This study identified subpopulations of patients with distinct drug sensitivity patterns linked to genetic and mutational profiles, and clinical outcomes.…”

Section: Approaches Allowing the Discovery Of New Effective Drug Combinationsmentioning

confidence: 99%

See 1 more Smart Citation

The Landscape of Signaling Pathways and Proteasome Inhibitors Combinations in Multiple Myeloma

Paradžik

Bandini

Mereu

et al. 2021

Cancers

View full text Add to dashboard Cite

Multiple myeloma is a malignancy of terminally differentiated plasma cells, characterized by an extreme genetic heterogeneity that poses great challenges for its successful treatment. Due to antibody overproduction, MM cells depend on the precise regulation of the protein degradation systems. Despite the success of PIs in MM treatment, resistance and adverse toxic effects such as peripheral neuropathy and cardiotoxicity could arise. To this end, the use of rational combinatorial treatments might allow lowering the dose of inhibitors and therefore, minimize their side-effects. Even though the suppression of different cellular pathways in combination with proteasome inhibitors have shown remarkable anti-myeloma activities in preclinical models, many of these promising combinations often failed in clinical trials. Substantial progress has been made by the simultaneous targeting of proteasome and different aspects of MM-associated immune dysfunctions. Moreover, targeting deranged metabolic hubs could represent a new avenue to identify effective therapeutic combinations with PIs. Finally, epigenetic drugs targeting either DNA methylation, histone modifiers/readers, or chromatin remodelers are showing pleiotropic anti-myeloma effects alone and in combination with PIs. We envisage that the positive outcome of patients will probably depend on the availability of more effective drug combinations and treatment of early MM stages. Therefore, the identification of sensitive targets and aberrant signaling pathways is instrumental for the development of new personalized therapies for MM patients.

show abstract

Section: Approaches Allowing the Discovery Of New Effective Drug Combinationsmentioning

confidence: 99%

“…This study identified subpopulations of patients with distinct drug sensitivity patterns linked to genetic and mutational profiles, and clinical outcomes. These patterns highlighted vulnerabilities that can be exploited for functional studies and combination therapy development [53].…”

Section: Approaches Allowing the Discovery Of New Effective Drug Combinationsmentioning

confidence: 99%

The Landscape of Signaling Pathways and Proteasome Inhibitors Combinations in Multiple Myeloma

Paradžik

Bandini

Mereu

et al. 2021

Cancers

View full text Add to dashboard Cite

show abstract

“…Bonolo de Campos et al evaluated 76 emerging FDA-approved oncology drugs in multiple myeloma and non-Hodgkin’s lymphoma cell lines [ 91 ]. It appeared that samples harboring a key oncogenic IRF4 (interferon regulatory factor 4) mutation were sensitive to the ALK inhibitors ceritinib and crizotinib.…”

Section: Combined Radiotherapy and Alk Inhibitors: An Approach To Overcome Resistance To Alk-targeted Therapies?mentioning

confidence: 99%

Combining Radiation Therapy with ALK Inhibitors in Anaplastic Lymphoma Kinase-Positive Non-Small Cell Lung Cancer (NSCLC): A Clinical and Preclinical Overview

Antoni

Burckel

Noël

2021

Cancers

View full text Add to dashboard Cite

Over the past years, the identification of genetic alterations in oncogenic drivers in non-small cell lung cancer (NSCLC) has significantly and favorably transformed the outcome of patients who can benefit from targeted therapies such as tyrosine kinase inhibitors. Among these genetic alterations, anaplastic lymphoma kinase (ALK) rearrangements were discovered in 2007 and are present in 3–5% of patients with NSCLC. In addition, radiotherapy remains one of the cornerstones of NSCLC treatment. Moreover, improvements in the field of radiotherapy with the use of hypofractionated or ablative stereotactic radiotherapy have led to a better outcome for localized or oligometastatic NSCLC. To date, the effects of the combination of ALK inhibitors and radiotherapy are unclear in terms of safety and efficacy but could potently improve treatment. In this manuscript, we provide a clinical and preclinical overview of combining radiation therapy with ALK inhibitors in anaplastic lymphoma kinase-positive non-small cell lung cancer.

show abstract

“…In multiple myeloma, several methods have shown this is feasible. [30][31][32][33] Building on these studies, we developed a method termed Myeloma Drug Sensitivity Testing (My-DST) that correlated well with subsequent clinical outcomes. 34 My-DST is a rapid ex vivo drug sensitivity assay that measures patient-specific sensitivity to a panel of agents currently in clinical use for treating multiple myeloma (Figure 1A).…”

Section: Personalized Medicine For Multiple Myelomamentioning

confidence: 99%

A case for improving frail patient outcomes in multiple myeloma with phenotype‐driven personalized medicine

et al. 2021

View full text Add to dashboard Cite

The treatment of older persons with cancer is fraught by a delicate balance of targeting the disease while avoiding treatment-related complications. "Personalized," or "precision" medicine approaches can ease this problem through more efficacious and less toxic treatments. Multiple myeloma epitomizes the struggle to balance treatment options and their complications, for it is an incurable disease afflicting a predominantly aged population, and treatment is administered on a continuous schedule with little or no breaks. Over the last two decades, advances in drug development have improved outcomes for younger, fit patients, but older, frail patients have not realized the same benefit. This could be related to the benefits of three drug combinations, when frail patients can often tolerate only two drugs at a time. In myeloma, personalized approaches have lagged behind some other malignancies due to its genetic complexity and a paucity of abnormalities with associated targeted therapies. In contrast, the disease is managed with an array of drugs that target phenotypic characteristics common in malignant plasma cells. To address the unmet need for personalized medicine in myeloma, we developed a functional approach by profiling the sensitivity of patients' myeloma to clinically available drugs. Through this, we observed that receiving at least two effective drugs portended better outcomes, leaving those patients who can only tolerate two drug regimens without room for error. We now describe a frail patient's case and their drug sensitivity profile to illustrate how personalized treatment could have led to an improved disease course. Personalized treatment could provide the greatest survival improvements to older adults with cancers, such as multiple myeloma, through avoiding undertreatment, limiting attrition through subsequent lines of therapy, reducing exposure to ineffective drugs and streamlining the management of relapses. Exploring these avenues is imperative to closing the gap of cancer-related mortality in older and frail persons.This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.

show abstract

“Direct to Drug” screening as a precision medicine tool in multiple myeloma

Cited by 22 publications

References 57 publications

The Landscape of Signaling Pathways and Proteasome Inhibitors Combinations in Multiple Myeloma

The Landscape of Signaling Pathways and Proteasome Inhibitors Combinations in Multiple Myeloma

Combining Radiation Therapy with ALK Inhibitors in Anaplastic Lymphoma Kinase-Positive Non-Small Cell Lung Cancer (NSCLC): A Clinical and Preclinical Overview

A case for improving frail patient outcomes in multiple myeloma with phenotype‐driven personalized medicine

Contact Info

Product

Resources

About