International Journal of Molecular Sciences

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24 pages, 729 KiB

Open AccessReview

Claudins in Cancer: A Current and Future Therapeutic Target

by Caroline Hana, Nyein Nyein Thaw Dar, Michael Galo Venegas and Michel Vulfovich

Int. J. Mol. Sci. 2024, 25(9), 4634; https://doi.org/10.3390/ijms25094634 - 24 Apr 2024

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Claudins are a family of 27 proteins that have an important role in the formation of tight junctions. They also have an important function in ion exchange, cell mobility, and the epithelial-to-mesenchymal transition, the latter being very important in cancer invasion and metastasis. [...] Read more.

Claudins are a family of 27 proteins that have an important role in the formation of tight junctions. They also have an important function in ion exchange, cell mobility, and the epithelial-to-mesenchymal transition, the latter being very important in cancer invasion and metastasis. Therapeutic targeting of claudins has been investigated to improve cancer outcomes. Recent evidence shows improved outcomes when combining monoclonal antibodies against claudin 18.2 with chemotherapy for patients with gastroesophageal junction cancer. Currently, chimeric antigen receptor T-cells targeting claudin 18 are under investigation. In this review, we will discuss the major functions of claudins, their distribution in the normal as well as cancerous tissues, and their effect in cancer metastasis, with a special focus on the therapeutic targeting of claudins to improve cancer outcomes. Full article

(This article belongs to the Special Issue From Basic Science to Treatment Strategies: Personalized Cancer Therapy)

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42 pages, 3297 KiB

Open AccessReview

Molecular Targeting of the Phosphoinositide-3-Protein Kinase (PI3K) Pathway across Various Cancers

by Khine S. Shan, Amalia Bonano-Rios, Nyein Wint Yee Theik, Atif Hussein and Marcelo Blaya

Int. J. Mol. Sci. 2024, 25(4), 1973; https://doi.org/10.3390/ijms25041973 - 6 Feb 2024

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Abstract

The dysregulation of the phosphatidylinositol-3-kinase (PI3K) pathway can lead to uncontrolled cellular growth and tumorigenesis. Targeting PI3K and its downstream substrates has been shown to be effective in preclinical studies and phase III trials with the approval of several PI3K pathway inhibitors by [...] Read more.

The dysregulation of the phosphatidylinositol-3-kinase (PI3K) pathway can lead to uncontrolled cellular growth and tumorigenesis. Targeting PI3K and its downstream substrates has been shown to be effective in preclinical studies and phase III trials with the approval of several PI3K pathway inhibitors by the Food and Drug Administration (FDA) over the past decade. However, the limited clinical efficacy of these inhibitors, intolerable toxicities, and acquired resistances limit the clinical application of PI3K inhibitors. This review discusses the PI3K signaling pathway, alterations in the PI3K pathway causing carcinogenesis, current and novel PI3K pathway inhibitors, adverse effects, resistance mechanisms, challenging issues, and future directions of PI3K pathway inhibitors. Full article

(This article belongs to the Special Issue From Basic Science to Treatment Strategies: Personalized Cancer Therapy)

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26 pages, 3152 KiB

Open AccessReview

Role of Immunotherapy in Sarcomas

by Shivani Dalal, Khine Swe Shan, Nyein Nyein Thaw Dar, Atif Hussein and Alejandra Ergle

Int. J. Mol. Sci. 2024, 25(2), 1266; https://doi.org/10.3390/ijms25021266 - 19 Jan 2024

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Abstract

Sarcomas are a group of malignancies of mesenchymal origin with a plethora of subtypes. Given the sheer heterogeneity of various subtypes and the rarity of the disease, the management of sarcomas has been challenging, with poor patient outcomes. Surgery, radiation therapy and chemotherapy [...] Read more.

Sarcomas are a group of malignancies of mesenchymal origin with a plethora of subtypes. Given the sheer heterogeneity of various subtypes and the rarity of the disease, the management of sarcomas has been challenging, with poor patient outcomes. Surgery, radiation therapy and chemotherapy have remained the backbone of treatment in patients with sarcoma. The introduction of immunotherapy has revolutionized the treatment of various solid and hematological malignancies. In this review, we discuss the basics of immunotherapy and the immune microenvironment in sarcomas; various modalities of immunotherapy, like immune checkpoint blockade, oncolytic viruses, cancer-targeted antibodies, vaccine therapy; and adoptive cell therapies like CAR T-cell therapy, T-cell therapy, and TCR therapy. Full article

(This article belongs to the Special Issue From Basic Science to Treatment Strategies: Personalized Cancer Therapy)

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14 pages, 1108 KiB

Open AccessReview

The Role of CD4/6 Inhibitors in Breast Cancer Treatment

by Luv Purohit, Can Jones, Teresita Gonzalez, Aurelio Castrellon and Atif Hussein

Int. J. Mol. Sci. 2024, 25(2), 1242; https://doi.org/10.3390/ijms25021242 - 19 Jan 2024

Cited by 1 | Viewed by 1355

Abstract

Over the last decade, treatment paradigms for breast cancer have undergone a renaissance, particularly in hormone-receptor-positive/HER2-negative breast cancer. These revolutionary therapies are based on the selective targeting of aberrancies within the cell cycle. This shift towards targeted therapies has also changed the landscape [...] Read more.

Over the last decade, treatment paradigms for breast cancer have undergone a renaissance, particularly in hormone-receptor-positive/HER2-negative breast cancer. These revolutionary therapies are based on the selective targeting of aberrancies within the cell cycle. This shift towards targeted therapies has also changed the landscape of disease monitoring. In this article, we will review the fundamentals of cell cycle progression in the context of the new cyclin-dependent kinase inhibitors. In addition to discussing the currently approved cyclin-dependent kinase inhibitors for breast cancer, we will explore the ongoing development and search for predictive biomarkers and modalities to monitor treatment. Full article

(This article belongs to the Special Issue From Basic Science to Treatment Strategies: Personalized Cancer Therapy)

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46 pages, 1721 KiB

Open AccessReview

Molecular Targeting of the Human Epidermal Growth Factor Receptor-2 (HER2) Genes across Various Cancers

by Elizabeth Rubin, Khine S. Shan, Shivani Dalal, Dieu Uyen Dao Vu, Adriana M. Milillo-Naraine, Delia Guaqueta and Alejandra Ergle

Int. J. Mol. Sci. 2024, 25(2), 1064; https://doi.org/10.3390/ijms25021064 - 15 Jan 2024

Cited by 2 | Viewed by 1386

Abstract

Human epidermal growth factor receptor 2 (HER2) belongs to the ErbB family, a group of four transmembrane glycoproteins with tyrosine kinase activity, all structurally related to epidermal growth factor receptor (EGFR). These tyrosine kinases are involved in the transmission of cellular signals controlling [...] Read more.

Human epidermal growth factor receptor 2 (HER2) belongs to the ErbB family, a group of four transmembrane glycoproteins with tyrosine kinase activity, all structurally related to epidermal growth factor receptor (EGFR). These tyrosine kinases are involved in the transmission of cellular signals controlling normal cell growth and differentiation. If this transmission goes awry, it can lead to dysregulated growth of the cell. HER2 specifically can be implicated in the pathogenesis of at least eight malignancies. HER2 positivity quickly became a well-characterized indicator of aggressiveness and poor prognosis, with high rates of disease progression and mortality. After realizing the implication of HER2, it first became investigated as a target for treatment in breast cancer, and later expanded to areas of research in other cancer types. To this day, the most therapeutic advancements of anti-HER2 therapy have been in breast cancer; however, there have been strong advancements made in the incorporation of anti-HER2 therapy in other cancer types as well. This comprehensive review dissects HER2 to its core, incorporating the most up to date information. The topics touched upon are discussed in detail and up to 200 published sources from the most highly recognized journals have been integrated. The importance of knowing about HER2 is exemplified by the groundbreaking advancements that have been made, and the change in treatment plans it has brought to the oncological world in the last twenty years. Since its groundbreaking discovery there have been significant breakthroughs in knowledge regarding the actual receptor, the receptors biology, its mechanism of action, and advancements in tests to detect HER2 and significant strides on how to best incorporate targeted treatment. Due to the success of this field thus far, the review concludes by discussing the future of novel anti-HER2 therapy currently in development that everyone should be aware of. Full article

(This article belongs to the Special Issue From Basic Science to Treatment Strategies: Personalized Cancer Therapy)

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18 pages, 1331 KiB

Open AccessReview

Folate Receptor Alpha—A Novel Approach to Cancer Therapy

by Teresita Gonzalez, Meri Muminovic, Olger Nano and Michel Vulfovich

Int. J. Mol. Sci. 2024, 25(2), 1046; https://doi.org/10.3390/ijms25021046 - 15 Jan 2024

Viewed by 3181

Abstract

Folate receptor α (FR) was discovered many decades ago, along with drugs that target intracellular folate metabolism, such as pemetrexed and methotrexate. Folate is taken up by the cell via this receptor, which also targeted by many cancer agents due to the over-expression [...] Read more.

Folate receptor α (FR) was discovered many decades ago, along with drugs that target intracellular folate metabolism, such as pemetrexed and methotrexate. Folate is taken up by the cell via this receptor, which also targeted by many cancer agents due to the over-expression of the receptor by cancer cells. FR is a membrane-bound glycosyl-phosphatidylinositol (GPI) anchor glycoprotein encoded by the folate receptor 1 (FOLR1) gene. FR plays a significant role in DNA synthesis, cell proliferation, DNA repair, and intracellular signaling, all of which are essential for tumorigenesis. FR is more prevalent in cancer cells compared to normal tissues, which makes it an excellent target for oncologic therapeutics. FRα is found in many cancer types, including ovarian cancer, non-small-cell lung cancer (NSCLC), and colon cancer. FR is widely used in antibody drug conjugates, small-molecule-drug conjugates, and chimeric antigen-receptor T cells. Current oncolytic therapeutics include mirvetuximab soravtansine, and ongoing clinical trials are underway to investigate chimeric antigen receptor T cells (CAR-T cells) and vaccines. Additionally, FRα has been used in a myriad of other applications, including as a tool in the identification of tumor types, and as a prognostic marker, as a surrogate of chemotherapy resistance. As such, FRα identification has become an essential part of precision medicine. Full article

(This article belongs to the Special Issue From Basic Science to Treatment Strategies: Personalized Cancer Therapy)

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29 pages, 1605 KiB

Open AccessReview

Molecular Targeting of the Fibroblast Growth Factor Receptor Pathway across Various Cancers

by Khine S. Shan, Shivani Dalal, Nyein Nyein Thaw Dar, Omani McLish, Matthew Salzberg and Brian A. Pico

Int. J. Mol. Sci. 2024, 25(2), 849; https://doi.org/10.3390/ijms25020849 - 10 Jan 2024

Cited by 1 | Viewed by 1288

Abstract

Fibroblast growth factor receptors (FGFRs) are a family of receptor tyrosine kinases that are involved in the regulation of cell proliferation, survival, and development. FGFR alterations including amplifications, fusions, rearrangements, and mutations can result in the downstream activation of tyrosine kinases, leading to [...] Read more.

Fibroblast growth factor receptors (FGFRs) are a family of receptor tyrosine kinases that are involved in the regulation of cell proliferation, survival, and development. FGFR alterations including amplifications, fusions, rearrangements, and mutations can result in the downstream activation of tyrosine kinases, leading to tumor development. Targeting these FGFR alterations has shown to be effective in treating cholangiocarcinoma, urothelial carcinoma, and myeloid/lymphoid neoplasms, and there are currently four FGFR inhibitors approved by the Food and Drug Administration (FDA). There have been developments in multiple agents targeting the FGFR pathway, including selective FGFR inhibitors, ligand traps, monoclonal antibodies, and antibody–drug conjugates. However, most of these agents have variable and low responses, with some intolerable toxicities and acquired resistances. This review will summarize previous clinical experiences and current developments in agents targeting the FGFR pathway, and will also discuss future directions for FGFR-targeting agents. Full article

(This article belongs to the Special Issue From Basic Science to Treatment Strategies: Personalized Cancer Therapy)

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25 pages, 751 KiB

Open AccessReview

Molecular Targeting of the BRAF Proto-Oncogene/Mitogen-Activated Protein Kinase (MAPK) Pathway across Cancers

by Khine S. Shan, Tauseef U. Rehman, Stan Ivanov, Gelenis Domingo and Luis E. Raez

Int. J. Mol. Sci. 2024, 25(1), 624; https://doi.org/10.3390/ijms25010624 - 3 Jan 2024

Cited by 1 | Viewed by 1803

Abstract

The mitogen-activated protein kinase (MAPK) pathway is essential for cellular proliferation, growth, and survival. Constitutive activation of this pathway by BRAF mutations can cause downstream activation of kinases, leading to uncontrolled cellular growth and carcinogenesis. Therefore, inhibition of BRAF and the downstream substrate [...] Read more.

The mitogen-activated protein kinase (MAPK) pathway is essential for cellular proliferation, growth, and survival. Constitutive activation of this pathway by BRAF mutations can cause downstream activation of kinases, leading to uncontrolled cellular growth and carcinogenesis. Therefore, inhibition of BRAF and the downstream substrate MEK has been shown to be effective in controlling tumor growth and proliferation. Over the last decade, several BRAF and MEK inhibitors have been investigated, ranging from primarily melanoma to various cancer types with BRAF alterations. This subsequently led to several Food and Drug Administration (FDA) approvals for BRAF/MEK inhibitors for melanoma, non-small cell lung cancer, anaplastic thyroid cancer, colorectal cancer, histiocytosis neoplasms, and finally, tumor-agnostic indications. Here, this comprehensive review will cover the developments of BRAF and MEK inhibitors from melanomas to tumor-agnostic indications, novel drugs, challenges, future directions, and the importance of those drugs in personalized medicine. Full article

(This article belongs to the Special Issue From Basic Science to Treatment Strategies: Personalized Cancer Therapy)

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