Tagged: multiple myeloma

Targeting Fatty Acid Binding Proteins in Multiple Myeloma

September 21, 2023

In a recent editorial, researchers discuss targeting fatty acid binding proteins to fight multiple myeloma.

Targeting Fatty Acid Binding Proteins in Multiple Myeloma

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Multiple myeloma (MM) is a type of blood cancer that affects plasma cells, which are responsible for producing antibodies. MM is characterized by the accumulation of abnormal plasma cells in the bone marrow, leading to bone damage, kidney failure, anemia, and increased susceptibility to infections. MM is a heterogeneous disease with different subtypes and genetic mutations that affect the prognosis and response to treatment. Therefore, there is a need for new biomarkers and therapeutic targets that can improve the outcomes of MM patients.

One of the potential targets that has recently emerged is the fatty acid binding protein (FABP) family. FABPs are proteins that bind and transport fatty acids, which are essential for energy production, cell signaling and membrane synthesis. FABPs are expressed in various tissues and organs, and have different roles depending on their location and type. There are nine members of the FABP family, but FABP5 seems to be the most relevant for MM.

In a recent editorial paper, researchers Heather Fairfield and Michaela R. Reagan from Maine Health Institute for Research, University of Maine and Tufts University School of Medicine summarized previous findings from their 2023 study and the current evidence on the role of FABPs in MM. On June 19, 2023, their editorial was published in Oncotarget, entitled, “The hope for targeting fatty acid binding proteins in multiple myeloma.”

“The FABPs hold promise as new therapeutic targets in multiple myeloma (MM), as described by our laboratory, and supported by in silico analyses [2] and other data [3, 4].”

Editorial Summary

The authors found that FABP5 expression is higher in MM cells than in normal plasma cells, and that high FABP5 levels are associated with worse survival and progression in MM patients. They also show that FABP inhibitors can reduce MM cell growth, survival and proliferation by affecting various pathways and processes, such as:

The unfolded protein response and ER stress response, which are activated by the high protein production in MM cells
The reactive oxygen species (ROS) generation, which can cause oxidative damage and apoptosis
The MYC oncogene expression and activity, which is essential for MM cell survival and proliferation
The mitochondrial function and metabolism, which are altered in MM cells to favor fatty acid oxidation
The DNA methylation patterns, which can affect gene expression and epigenetic regulation
The immune cell infiltration and cytokine production in the bone marrow microenvironment, which can modulate the tumor-host interactions

The researchers also highlighted findings from other studies that support the importance of FABPs in MM. For example, Jia et al. found that FABP5 expression correlates with immune cell changes in the MM microenvironment. Liang et al. found that FABP4 expression is increased in MM patients and that FABP4 knockout or inhibition can improve survival and reduce tumor burden in mice models.

“We reported studies showing either decreased tumor burden or no effect of FABP inhibition in vivo, and thus further optimization of in vivo targeting of FABPs, FABP inhibitor design, or overcoming FABP inhibitor resistance in the bone marrow is still required before translation to the clinic can materialize [1].”

Conclusion

The authors conclude that FABPs are promising prognostic markers and therapeutic targets in MM, and that further research is needed to elucidate their mechanisms of action and to develop specific inhibitors. They also suggest that targeting both tumor cell-derived and microenvironment-derived FABPs may be more effective than targeting either one alone.

This editorial provides a concise overview of the current state of knowledge on FABPs in MM, and highlights the potential benefits of targeting them for MM treatment. It also raises some interesting questions for future research, such as:

How do FABPs interact with other metabolic pathways and regulators in MM cells?
How do FABPs affect the bone remodeling process and osteolytic lesions in MM?
How do FABPs influence the drug resistance and relapse in MM?
How do different types of FABPs cooperate or compete with each other in MM?
How can FABP inhibitors be combined with other therapies for optimal efficacy and safety?

“Still, we are hopeful that by targeting FABPs, or following the science to other related pathways, it will be possible to revolutionize the therapy regimes currently used for MM patients.”

Click here to read the full editorial in Oncotarget.

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Oncotarget is an open-access, peer-reviewed journal that has published primarily oncology-focused research papers since 2010. These papers are available to readers (at no cost and free of subscription barriers) in a continuous publishing format at Oncotarget.com. Oncotarget is indexed/archived on MEDLINE / PMC / PubMed.

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The Importance of CD56 in the Fight Against Multiple Myeloma

February 2, 2023

In a new Oncotarget editorial, researchers discussed their study on CD56 in multiple myeloma.

Figure 1: Graphical representation of the main findings of the summarized paper.

The Trending With Impact series highlights Oncotarget publications attracting higher visibility among readers around the world online, in the news, and on social media—beyond normal readership levels. Look for future science news about the latest trending publications here, and at Oncotarget.com.

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Multiple myeloma (MM) is a type of blood cancer that affects plasma cells in the bone marrow. These plasma cells, which are responsible for producing antibodies, become abnormal and begin to grow uncontrollably. This results in a buildup of abnormal cells in the bone marrow, leading to decreased production of healthy blood cells, bone damage and a host of other symptoms. MM is incredibly heterogenic, and this variability often leads to unsatisfactory long-term treatment outcomes in many patients with MM. Targets for new treatments and biomarkers of response are needed to improve patient outcomes.

In a new editorial paper published in Oncotarget, researchers Francesca Cottini and Don Benson from The Ohio State University discuss a 2022 research paper they co-authored in which CD56 (or neuronal cell adhesion molecule; NCAM1) was thoroughly described as a biomarker and therapeutic target in multiple myeloma. On January 26, 2023, their editorial about this research paper was published in Oncotarget, entitled, “To be or not to be: the role of CD56 in multiple myeloma.”

“Among others, CD56 is present at variable levels in approximately 70% of patients with multiple myeloma; however, very little is known about CD56 role in multiple myeloma.” (2022 Cottini et al.)

CD56 in MM

The role of CD56 in multiple myeloma is a topic of ongoing research and discussion among scientists and medical professionals. CD56 is a protein that is found on the surface of many different cell types, including plasma cells. Researchers have demonstrated that it plays a key role in the development and progression of multiple myeloma, making it a potential target for new treatments.

One of the main functions of CD56 is to regulate the growth and survival of plasma cells. In normal cells, CD56 helps to prevent uncontrolled growth and division of cells. However, in multiple myeloma cells, CD56 appears to play a different role. Research has shown that CD56 is overexpressed in multiple myeloma cells, leading to an increase in cell growth and division.

Additionally, CD56 has been found to play a role in the immune system’s response to cancer cells. In multiple myeloma, CD56 can suppress the immune system’s response to the abnormal cells, allowing them to continue growing unchecked. This is why multiple myeloma is often resistant to traditional cancer treatments such as chemotherapy and radiation.

Targeting CD56 in MM

There are currently several strategies being explored to target CD56 in multiple myeloma. One approach is to use drugs that block the function of CD56, in order to prevent it from promoting cell growth and division. Another approach is to use immunotherapies that stimulate the immune system to attack the abnormal cells. This can help to overcome the suppression of the immune system by CD56 and lead to more effective cancer treatment.

There is also research being conducted into the use of CAR T-cell therapy. CAR T-cell therapy involves genetically modifying a patient’s own immune cells to attack the cancer cells. In this type of therapy, the immune cells are modified to target CD56 specifically, which allows them to attack and destroy the multiple myeloma cells more effectively.

Cottini et al.

In this editorial, the researchers discuss their study, which looked at CD56-expressing clonal MM cells in more than 700 patients at the time of MM diagnosis. The researchers found that the size of these cells varied between patients and increased as the disease worsened. Results demonstrated that having a large amount of these cells was linked to worse outcomes and shorter responses to treatment.

The study then looked at how changing the expression of CD56 affected the behavior of MM cells and found that it influenced cell growth and survival. They also discovered that a protein called RSK2 and another called CREB1 play a role in this process. They then tested medicines to block these proteins and found that they were effective in killing MM cells that had a high amount of CD56, but not as much in those with low levels of CD56.

“The authors’ preclinical data support the use of synthetic lethal approaches by CREB1/RSK2 inhibition in combination with lenalidomide, as a strategy to overcome CRBN downregulation in CD56-high MM.”

Conclusion

“In summary, this study provides a detailed description of CD56 role in MM, opening new clinically relevant scenarios.”

The role of CD56 in multiple myeloma is complex and still not fully understood. However, the researchers who wrote this editorial aimed to clearly define CD56’s key role in the development and progression of this disease, making it a potential target for new treatments. By better understanding the function of CD56, scientists and medical professionals can continue to develop new and innovative therapies to improve the lives of those affected by multiple myeloma.

“Since the majority of clinical laboratories have the capability to perform CD56 staining and define a threshold of positivity, CD56 expression can be both a prognostic and predictive factor of response to therapies, an unmet need in the MM field (Figure 1).”

Click here to read the full editorial published in Oncotarget.

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Synergy of HDACi, PARPi and Chemotherapeutics Against Blood Cancer

October 19, 2022

Researchers investigated the efficacy of HDAC inhibitors in combination with PARP inhibitors and chemotherapeutic drugs in multiple blood cancer cell lines.

Synergy of HDACi, PARPi and Chemotherapeutics Against Blood Cancer

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Chromatin constitutes chromosomes in eukaryotic cells and comprises DNA and proteins. Chromosomes produce proteins and enzymes that are essential for cellular function and maintenance, including DNA repair. A critical process for DNA repair is poly(ADP-ribosyl)ation, or PARylation.

PARylation is triggered by poly(ADP ribose) polymerase (PARP) enzymes. When DNA becomes damaged, PARP enzymes bind to the damaged location in the cell. In cancer cells, however, this natural process can be counterproductive in respect to cancer treatment. PARylation can produce DNA repair mechanisms in cancer cells that can lead to cell death evasion and even drug resistance. Inhibiting PARylation may be a viable therapeutic strategy for cancer treatment.

HDAC Inhibitors

Histones, the main proteins that constitute chromatin, undergo post-translational modifications that regulate gene expression. Histone acetylation is an important epigenetic process that affects gene expression by relaxing the chromatin structure, making chromatin remodeling more feasible. Histone deacetylases (HDACs) are enzymes that can have the opposite effect. Histone deacetylation makes the chromatin more compact and difficult to remodel. The overexpression of HDAC has also been associated with tumorigenesis. Histone deacetylase inhibitors (HDACi) are a class of therapeutics that have shown promise in the treatment of hematologic malignancies (blood cancer) and solid tumors.

“Overexpression of HDACs has been associated with tumorigenesis by down-regulation of tumor suppressor genes [3, 4]; hence, HDAC inhibitors (HDACi) including vorinostat (SAHA), romidepsin (Rom), panobinostat (Pano) and belinostat have been approved by the United States Food and Drug Administration for the treatment of hematologic and other malignancies [5]. These inhibitors restore appropriate gene expression, resulting in induction of cell differentiation, cell cycle arrest and apoptosis [6].”

The Study

In a new study, researchers Benigno C. Valdez, Yago Nieto, Bin Yuan, David Murray, and Borje S. Andersson from the Department of Stem Cell Transplantation and Cellular Therapy at the University of Texas MD Anderson Cancer Center and the Cross Cancer Institute’s Department of Experimental Oncology at the University of Alberta investigate the efficacy of HDACi in combination with PARP inhibitors (PARPi) and chemotherapeutic drugs to treat hematologic cancer. On October 14, 2022, their research paper was published in Volume 13 of Oncotarget, entitled, “HDAC inhibitors suppress protein poly(ADP-ribosyl)ation and DNA repair protein levels and phosphorylation status in hematologic cancer cells: implications for their use in combination with PARP inhibitors and chemotherapeutic drugs.”

“Despite their preclinical efficacy, HDACi do not seem to be clinically highly effective as monotherapy, and potentially more effective anti-tumor activity is observed when they are combined with other anti-cancer drugs [7–9].”

Studies on the interactions of HDACi with PARPi in cancers of the blood are limited, especially when combined with chemotherapeutic agents. The researchers used a panel of hematologic cancer cell lines (acute myeloid leukemia, T-cell acute lymphoblastic leukemia, chronic myeloid leukemia, and multiple myeloma) and patient-derived cell samples to study the effect of HDACi (including SAHA (Vorinostat), panobinostat (Pano), romidepsin (Rom) and trichostatin A (TSA)) on PARylation. In addition, the team looked at the efficacy of HDACi combined with PARPi, including Olaparib (Ola) and niraparib (Npb), and with chemotherapeutic agents gemcitabine (Gem), busulfan (Bu) and melphalan (Mel).

Results

The researchers found that hematologic cancer cell lines and patient-derived cell samples exposed to various HDACi resulted in a significant caspase-independent inhibition of protein PARylation. HDACi-mediated inhibition of protein PARylation was mainly catalyzed by PARP1. These findings suggest that HDACi could potentially be used in combination with PARP inhibitors and chemotherapeutic drugs to treat blood cancers.

“Our results indicate that the anti-tumor efficacy of HDACi is partly due to down-regulation of PARylation, which negatively affects the status of DNA repair proteins. This repair inhibition, combined with the high levels of oxidative and DNA replication stress characteristic of cancer cells, could have conferred these hematologic cancer cells not only with a high sensitivity to HDACi but also with a heightened dependence on PARP and therefore with extreme sensitivity to combined HDACi/PARPi treatment and, by extension, to their combination with conventional DNA-damaging chemotherapeutic agents. The observed synergism of these drugs could have a major significance in improving treatment of these cancers.”

Conclusion

HDACi drugs can inhibit PARylation. The combination of HDACi-mediated inhibition of PARylation was complemented by PARPi and chemotherapeutic agents in multiple blood cancer cell lines. The efficacy of this combined treatment was superior to that of any single agent, supporting the further clinical development of HDACi in cancer therapy. These findings could potentially be used to improve the treatment of hematologic cancers.

“In conclusion, our results provide a molecular explanation for the HDACi-mediated inhibition of DNA repair in hematologic cancer cells and support the combinatorial application of HDACi, PARPi and chemotherapeutic agents for the treatment of hematologic malignancies.”

Click here to read the full research paper published by Oncotarget.

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Trending With Impact: Adjunct Virotherapy Fights Multiple Myeloma

March 17, 2022

Researchers investigated using oncolytic viruses to treat multiple myeloma—alone and in a combination approach.

3D red blood cells in vein — 3D red blood cells

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Multiple myeloma (MM) is a currently incurable cancer of blood plasma cells. Autologous stem cell transplantation (ASCT) has had efficacious results among eligible patients. However, even after ASCT, a significant number of patients continue to relapse and become resistant to current standard therapies.

A promising new method to treat blood cancers is a form of immunotherapy called virotherapy. Oncolytic viruses are uniquely capable of being reprogrammed to selectively infect and kill various cancer cells without infecting or damaging normal cells in host organisms, including mice and humans. Researchers from Arizona State University, Emory University and the Mayo Clinic (in Scottsdale, Arizona) had previously experimented with using the oncolytic myxoma virus (MYXV) to treat MM. In nature, MYXV only affects rabbits and is innocuous in mice and humans. They found that MYXVs delivered through stem cell transplantation can eliminate some residual MM cells in the Balb/c mouse model.

“Recently, we reported that ex vivo virotherapy with oncolytic myxoma virus (MYXV) improved MM-free survival in an autologous-transplant Balb/c mouse model.”

However, the researchers found that Balb/c mice may not be ideal models for MM. They observed that the behavior of MM in Balb/c mice did not quite reflect the development, clinical manifestation and localization of MM observed in human patients. Therefore, the team conducted a new study of MYXVs in the Vk*MYC transplantable C57BL/6 mouse MM model. Their trending research paper was published in Oncotarget on March 3, 2022, and entitled, “Transplantation of autologous bone marrow pre-loaded ex vivo with oncolytic myxoma virus is efficacious against drug-resistant Vk*MYC mouse myeloma.“

The Study

“In this study, we used the Vk*MYC MM model because it faithfully recapitulates the localization of the myeloma disease within the bone marrow as well as the clinical manifestation of the disease including bone damage (paralysis), renal failure [9, 12].”

A bortezomib-resistant multiple myeloma murine cell line was examined in this study, named Vk12598. Three different strains of MYXV were tested here: vMyx-M093L-Venus, vMyx-M135KO and vMyx-hTNF. The vMyx-M093L-Venus is a wild-type MYXV that expresses Venus-tagged M093 protein as a virion component. The vMyx-M135KO virus is an unarmed and attenuated recombinant MYXV, in which the M135 gene has been deleted and the green fluorescent protein (GFP) has been inserted. The vMyx-hTNF strain is genetically modified, or “armed”, to express human tumor necrosis factor (TNF). TNF is a cytokine that induces apoptosis in various cancer cells.

First, the researchers examined the in vitro ability of these three MYXVs to bind to the Vk12598 cells in culture media. These results were then tested in vivo by first injecting the C57BL/6 mice with Vk12598 cells. Vk12598 cells were seeded for three weeks to allow the MM to progress in the mice. Then, some mice were treated with either cyclophosphamide (a common chemotherapeutic drug used to treat MM) or the compounds LCL161 and α-PD-1. Next, bone marrow cells were loaded with either vMyx-M135KO or vMyx-hTNF and transplanted into the mice.

The Results

In vitro, the researchers found that all three MYXVs did indeed bind to, infect and compromise the viability of the BOR-resistant MM cells in a relatively short period of time. In vivo, the results demonstrated that, alone, autologous bone marrow leukocytes armed ex vivo with the MYXVs (BM/MYXV) exhibited moderate therapeutic effects against the MM cells. This indicated that BM/MYXV has potential as an adjunct therapy against the MM. While little synergy was observed between Cyclophosphamide (Cy) and BM/MYXV, Cy in combination with BM/vMyx-M135KO delayed the onset of myeloma in the mice more than Cy combined with BM/vMyx-hTNF. The researchers note that these results indicate the TNF transgene may have actually interfered with efficacy.

The authors also observed a better synergistic ability between BM/vMyx-M135KO and LCL161 with α-PD-1 to control the progression of MM. This combination resulted in a significant improvement in survival rates and decreased tumor burden. When surviving mice were re-introduced to Vk12598 cells, the researchers found that they had developed acquired anti-MM immunity.

Conclusion

“Together, we show promising results in terms of therapeutic benefits of delivering oncolytic MYXV via carrier cells from autologous BM transplants, both alone or in combination with LCL161 and α-PD-1 against drug-resistant MM cells in vivo. To our knowledge, these are the first results showing therapeutic benefits of oncolytic MYXV to control and even eradicate established drug-resistant MM cells in a preclinical murine model that has previously shown excellent concordance with predicting clinical efficacy in human MM patients.”

Click here to read the full research paper published by Oncotarget.

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