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A special issue of Journal of Personalized Medicine (ISSN 2075-4426). This special issue belongs to the section "Mechanisms of Diseases".

Deadline for manuscript submissions: closed (10 May 2021) | Viewed by 48640

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Dr. Ari VanderWalde

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Guest Editor

Director of Clinical Research, West Cancer Center and Research Institute, Memphis, TN, USA
Interests: clinical trials; drug development; immune therapy; molecular targeted therapy; melanoma; biomedical ethics; medical oncology; outcomes research; healthcare management

Special Issue Information

Dear colleagues,

Nowhere is the explosion in comprehensive genomic testing more evident than in oncology. Multiple consensus guidelines now recommend molecular testing as the standard of care for most metastatic tumors. To aid in the advancement of this rapidly changing field, we intend this Special Issue of JPM to focus on technical developments in the genomic profiling of cancer, detail promising somatic alterations that either are, or have a high likelihood of being, relevant in the near future, and to address issues related to the pricing and value of these tests.

The last few years have seen the cost of molecular testing decrease by orders of magnitude. In 2018, we saw the first “site-agnostic” drug approvals in cancer (for microsatellite unstable cancer (PD-1 inhibitors) and NTRK-fusions (TRK inhibitors)). Research on targetable mutations, determination of genetic “signatures” that can use multiple individual genes/pathways, development of targeted therapy, and insight into the value of new technology remains at the cutting edge of research in this field. We are soliciting papers that present new technologies to assess predictive biomarkers in cancer, original research (pre-clinical or clinical) that demonstrates promise for particular targeted therapies in cancer, and articles that explore the clinical and financial impacts of this paradigmatic shift in cancer diagnostics and treatment.

Dr. Ari VanderWalde
Guest Editor

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Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Journal of Personalized Medicine is an international peer-reviewed open access monthly journal published by MDPI.

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Keywords

cancer genomic profiling
hereditary cancer risk
cancer biomarkers
targeted therapy
treatment decision-making
next generation sequencing
whole transcriptome

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Published Papers (12 papers)

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Editorial

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3 pages, 176 KiB

Open AccessEditorial

Personalized Medicine in Oncology; a Special Issue of the Journal of Personalized Medicine

by Ari VanderWalde

J. Pers. Med. 2021, 11(7), 632; https://doi.org/10.3390/jpm11070632 - 2 Jul 2021

Viewed by 2242

Abstract

Nowhere is the explosion in comprehensive genomic testing more evident than in oncology [...] Full article

(This article belongs to the Special Issue Personalized Medicine in Oncology)

Research

Jump to: Editorial, Review, Other

18 pages, 3784 KiB

Open AccessArticle

Endothelin-1 as a Mediator of Heme Oxygenase-1-Induced Stemness in Colorectal Cancer: Influence of p53

by Sandra Ríos-Arrabal, Jose D. Puentes-Pardo, Sara Moreno-SanJuan, Ágata Szuba, Jorge Casado, María García-Costela, Julia Escudero-Feliu, Michela Verbeni, Carlos Cano, Cristina González-Puga, Alicia Martín-Lagos Maldonado, Ángel Carazo and Josefa León

J. Pers. Med. 2021, 11(6), 509; https://doi.org/10.3390/jpm11060509 - 4 Jun 2021

Cited by 8 | Viewed by 3517

Abstract

Heme oxygenase-1 (HO-1) is an antioxidant protein implicated in tumor progression, metastasis, and resistance to therapy. Elevated HO-1 expression is associated with stemness in several types of cancer, although this aspect has not yet been studied in colorectal cancer (CRC). Using an in vitro model, we demonstrated that HO-1 overexpression regulates stemness and resistance to 5-FU treatment, regardless of p53. In samples from CRC patients, HO-1 and endothelin converting enzyme-1 (ECE-1) expression correlated significantly, and p53 had no influence on this result. Carbon monoxide (CO) activated the ECE-1/endothelin-1 (ET-1) pathway, which could account for the protumoral effects of HO-1 in p53 wild-type cells, as demonstrated after treatment with bosentan (an antagonist of both ETRA and ETRB endothelin-1 receptors). Surprisingly, in cells with a non-active p53 or a mutated p53 with gain-of-function, ECE-1-produced ET-1 acted as a protective molecule, since treatment with bosentan led to increased efficiency for spheres formation and percentage of cancer stem cells (CSCs) markers. In these cells, HO-1 could activate or inactivate certain unknown routes that could induce these contrary responses after treatment with bosentan in our cell model. However more research is warranted to confirm these results. Patients carrying tumors with a high expression of both HO-1 and ECE-1 and a non-wild-type p53 should be considered for HO-1 based-therapies instead of ET-1 antagonists-based ones. Full article

(This article belongs to the Special Issue Personalized Medicine in Oncology)

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12 pages, 14453 KiB

Open AccessArticle

Tumor Infiltrating Neutrophils Are Frequently Found in Adenocarcinomas of the Biliary Tract and Their Precursor Lesions with Possible Impact on Prognosis

by Vittorio Branchi, Benedict Jürgensen, Laura Esser, Maria Gonzalez-Carmona, Tobias J. Weismüller, Christian P. Strassburg, Jonas Henn, Alexander Semaan, Philipp Lingohr, Steffen Manekeller, Glen Kristiansen, Jörg C. Kalff, Marieta I. Toma and Hanno Matthaei

J. Pers. Med. 2021, 11(3), 233; https://doi.org/10.3390/jpm11030233 - 23 Mar 2021

Cited by 6 | Viewed by 2763

Abstract

Biliary tract cancer (BTC) is characterized by an intense stromal reaction and a complex landscape of infiltrating immune cells. Evidence is emerging that tumor-infiltrating neutrophils (TINs) have an impact on carcinogenesis and tumor progression. TINs have also been associated with outcomes in various solid malignant tumors but their possible clinical role in BTC is largely unknown. Tissue samples from patients with sporadic BTC (“spBTC” cohort, N = 53) and BTC in association with primary sclerosing cholangitis (“PSC-BTC” cohort, N = 7) were collected. Furthermore, tissue samples from 27 patients with PSC who underwent liver transplantation (“PSC-LTX” cohort) were investigated. All specimens were assessed for TIN density in invasive and precancerous lesions (biliary intraepithelial neoplasia, BilIN). Most spBTC showed low TIN density (LD, 61%). High TIN density (HD) was detected in 16% of the tumors, whereas 23% were classified as intermediate density (ID); the majority of both HD and ID groups were in T1–T2 tumors (83% and 100%, p = 0.012). TIN density in BilIN lesions did not significantly differ among the three groups. The HD group had a mean overall survival (OS) of 53.5 months, whereas the mean OS in the LD and ID groups was significantly shorter (LD 29.5 months vs. ID 24.6 months, log-rank p < 0.05). The results of this study underline the possible prognostic relevance of TINs in BTC and stress the complexity of the immune cell landscape in BTC. The prognostic relevance of TINs suggests a key regulator role in inflammation and immune landscape in BTC. Full article

(This article belongs to the Special Issue Personalized Medicine in Oncology)

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8 pages, 907 KiB

Open AccessArticle

Gender Differences in Patients with Metastatic Pancreatic Cancer Who Received FOLFIRINOX

by Jinkook Kim, Eunjeong Ji, Kwangrok Jung, In Ho Jung, Jaewoo Park, Jong-Chan Lee, Jin Won Kim, Jin-Hyeok Hwang and Jaihwan Kim

J. Pers. Med. 2021, 11(2), 83; https://doi.org/10.3390/jpm11020083 - 30 Jan 2021

Cited by 13 | Viewed by 2408

Abstract

Background: The combination of 5-fluorouracil, leucovorin, irinotecan, and oxaliplatin (FOLFIRINOX) is a very effective chemotherapeutic regimen for unresectable pancreatic cancer. Previous studies have reported that female gender may be a predictor of a better response to FOLFIRINOX. This study was aimed at investigating the clinical outcomes and dose modification patterns of FOLFIRINOX by gender. Methods: Patients with metastatic pancreatic cancer (MPC) who began FOLFIRINOX as the first-line therapy at Seoul National University Bundang Hospital between 2013 and 2018 were enrolled. The patients received at least four chemotherapy cycles. Local regression and a linear mixed model were used to analyze dose modification patterns by gender. Results: Ninety-seven patients with MPC (54 men; 43 women) were enrolled. In the first FOLFIRINOX cycle, there were significant differences in age and body surface area between the genders (58.8 (men) and 64.9 years (women), p = 0.005; 1.7 (men) and 1.6 m² (women), p < 0.001, respectively). The median progression-free survival (PFS) and overall survival (OS) were 10.8 and 18.0 months, respectively. There was a trend of longer PFS (10.3 (men) and 11.9 months (women), p = 0.153) and a significantly longer OS (17.9 (men) and 25.9 months (women), p = 0.019) in female patients. During the first year of FOLFIRINOX treatment, there was a significant difference of the age-corrected dose reduction pattern by gender (a mean of 95.6% dose at the initial cycle and −0.35% of dose reduction per week in men versus a mean of 90.7% dose at the initial cycle and −0.53% of dose reduction per week in women, p-value of the slope: <0.001). There was no difference in the adverse event rates between the genders. Conclusions: Female patients showed longer OS despite a more rapid dose reduction during each cycle. Gender differences should be considered during FOLFIRINOX treatment. Full article

(This article belongs to the Special Issue Personalized Medicine in Oncology)

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9 pages, 815 KiB

Open AccessArticle

Establishment of a Molecular Tumor Board (MTB) and Uptake of Recommendations in a Community Setting

by Ari VanderWalde, Axel Grothey, Daniel Vaena, Gregory Vidal, Adam ElNaggar, Gabriella Bufalino and Lee Schwartzberg

J. Pers. Med. 2020, 10(4), 252; https://doi.org/10.3390/jpm10040252 - 27 Nov 2020

Cited by 25 | Viewed by 4117

Abstract

In the precision medicine era, molecular testing in advanced cancer is foundational to patient management. Molecular tumor boards (MTBs) can be effective in processing comprehensive genomic profiling (CGP) results and providing expert recommendations. We assessed an MTB and its role in a community setting. This retrospective analysis included patients with MTB recommendations at a community-based oncology practice January 2015 to December 2018; exclusions were death within 60 days of the MTB and/or no metastatic disease. Potentially actionable genomic alterations from CGP (immunohistochemistry, in-situ hybridization, next-generation sequencing) were reviewed bi-weekly by MTB practice experts, pathologists, genetic counselors, and other support staff, and clinical care recommendations were provided. Subsequent chart reviews determined implementation rates of recommendations. In 613 patients, the most common cancers were lung (23%), breast (19%), and colorectal (17%); others included ovarian, endometrial, bladder, and melanoma. Patients received 837 actionable recommendations: standard therapy (37%), clinical trial (31%), germline testing and genetic counseling (17%), off-label therapy (10%), subspecialty multidisciplinary tumor board review (2%), and advice for classifying tumor of unknown origin (2%). Of these recommendations, 36% to 78% were followed by the treating physician. For clinical trial recommendations (n = 262), 13% of patients enrolled in a clinical trial. The median time between CPG result availability and MTB presentation was 12 days. A community oncology-based comprehensive and high-throughput MTB provided useful clinical guidance in various treatment domains within an acceptable timeframe for patients with cancer in a large community setting. Full article

(This article belongs to the Special Issue Personalized Medicine in Oncology)

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15 pages, 4549 KiB

Open AccessArticle

Integrin-Linked Kinase Is a Novel Therapeutic Target in Ovarian Cancer

by Michael A. Ulm, Tiffany M. Redfern, Ben R. Wilson, Suriyan Ponnusamy, Sarah Asemota, Patrick W. Blackburn, Yinan Wang, Adam C. ElNaggar and Ramesh Narayanan

J. Pers. Med. 2020, 10(4), 246; https://doi.org/10.3390/jpm10040246 - 26 Nov 2020

Cited by 4 | Viewed by 2417

Abstract

Objective: The objective of this study is to identify and validate novel therapeutic target(s) in ovarian cancer. Background: Development of targeted therapeutics in ovarian cancer has been limited by molecular heterogeneity. Although gene expression datasets are available, most of them lack appropriate pair-matched controls to define the alterations that result in the transformation of normal ovarian cells to cancerous cells. Methods: We used microarray to compare the gene expression of treatment-naïve ovarian cancer tissue samples to pair-matched normal adjacent ovarian tissue from 24 patients. Ingenuity Pathway Analysis (IPA) was used to identify target pathways for further analysis. Integrin-linked kinase (ILK) expression in SKOV3 and OV90 cells was determined using Western blot. ILK was knocked down using CRISPR/Cas9 constructs. Subcutaneous xenograft study to determine the effect of ILK knockdown on tumor growth was performed in NOD SCID gamma mice. Results: Significant upregulation of the ILK pathway was identified in 22 of the 24 cancer specimens, identifying it as a potential player that could contribute to the transformation of normal ovarian cells to cancerous cells. Knockdown of ILK in SKOV3 cells resulted in decreased cell proliferation and tumor growth, and inhibition of downstream kinase, AKT (protein kinase B). These results were further validated using an ILK-1 chemical inhibitor, compound 22. Conclusion: Our initial findings validate ILK as a potential therapeutic target for molecular inhibition in ovarian cancer, which warrants further investigation. Full article

(This article belongs to the Special Issue Personalized Medicine in Oncology)

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17 pages, 941 KiB

Open AccessArticle

Targeted Therapy Recommendations for Therapy Refractory Solid Tumors—Data from the Real-World Precision Medicine Platform MONDTI

by Hossein Taghizadeh, Matthias Unseld, Martina Spalt, Robert M. Mader, Leonhard Müllauer, Thorsten Fuereder, Markus Raderer, Maria Sibilia, Mir Alireza Hoda, Stefanie Aust, Stephan Polterauer, Wolfgang Lamm, Rupert Bartsch, Matthias Preusser, Kautzky-Willer A. and Gerald W. Prager

J. Pers. Med. 2020, 10(4), 188; https://doi.org/10.3390/jpm10040188 - 23 Oct 2020

Cited by 7 | Viewed by 2903

Abstract

Advanced therapy-refractory solid tumors bear a dismal prognosis and constitute a major challenge in offering effective treatment strategies. In this real-world retrospective analysis of our precision medicine platform MONDTI, we describe the molecular profile of 554 patients diagnosed with 17 different types of advanced solid tumors after failure of all standard treatment options. In 304 cases (54.9% of all patients), a molecular-driven targeted therapy approach could be recommended, with a recommendation rate above 50% in 12 tumor entities. The three highest rates for therapy recommendation per tumor classification were observed in urologic malignancies (90.0%), mesothelioma (78.6%), and male reproductive cancers (71.4%). Tumor type (p = 0.46), expression of p-mTOR (p = 0.011), expression of EGFR (p = 0.046), and expression of PD-L1 (p = 0.023) had a significant impact on the targeted therapy recommendation rate. Therapy recommendations were significantly more often issued for men (p = 0.015) due to gender-specific differences in the molecular profiles of patients with head and neck cancer and malignant mesothelioma. This analysis demonstrates that precision medicine was feasible and provided the basis for molecular-driven therapy recommendations in patients with advanced therapy refractory solid tumors. Full article

(This article belongs to the Special Issue Personalized Medicine in Oncology)

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Review

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33 pages, 509 KiB

Open AccessReview

Precision Medicine in Oncology: A Review of Multi-Tumor Actionable Molecular Targets with an Emphasis on Non-Small Cell Lung Cancer

by Matthew K. Stein, Oluchukwu Oluoha, Kruti Patel and Ari VanderWalde

J. Pers. Med. 2021, 11(6), 518; https://doi.org/10.3390/jpm11060518 - 5 Jun 2021

Cited by 18 | Viewed by 5399

Abstract

Precision medicine is essential for the modern care of a patient with cancer. Comprehensive molecular profiling of the tumor itself is necessary to determine the presence or absence of certain targetable abnormalities or biomarkers. In particular, lung cancer is a disease for which targetable genomic alterations will soon guide therapy in the majority of cases. In this comprehensive review of solid tumor-based biomarkers, we describe the genomic alterations for which targeted agents have been approved by the United States Food and Drug Administration (FDA). While focusing on alterations leading to approvals in a tumor-agnostic fashion (MSI-h, TMB-h, NTRK) and on those alterations with approvals in multiple malignancies (BRAF, ERBB2, RET, BRCA, PD-L1), we also describe several biomarkers or indications that are likely to lead to an approved drug in the near future (e.g., KRAS G12C, PD-L1 amplification, HER2 overexpression in colon cancer, HER2 mutations in lung cancer). Finally, we detail the current landscape of additional actionable alterations (EGFR, ALK, ROS1, MET) in lung cancer, a biomarker-rich malignancy that has greatly benefitted from the precision oncology revolution. Full article

(This article belongs to the Special Issue Personalized Medicine in Oncology)

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18 pages, 685 KiB

Open AccessReview

Biomarker Development for Metastatic Renal Cell Carcinoma: Omics, Antigens, T-cells, and Beyond

by Benjamin Miron, David Xu and Matthew Zibelman

J. Pers. Med. 2020, 10(4), 225; https://doi.org/10.3390/jpm10040225 - 13 Nov 2020

Cited by 7 | Viewed by 4494

Abstract

The treatment of metastatic renal cell carcinoma has evolved quickly over the last few years from a disease managed primarily with sequential oral tyrosine kinase inhibitors (TKIs) targeting the vascular endothelial growth factor (VEGF) pathway, to now with a combination of therapies incorporating immune checkpoint blockade (ICB). Patient outcomes have improved with these innovations, however, controversy persists regarding optimal sequence and patient selection amongst the available combinations. Ideally, predictive biomarkers would aid in guiding treatment decisions and personalizing care. However, clinically-actionable biomarkers have remained elusive. We aim to review the available evidence regarding biomarkers for both TKIs and ICB and will present where the field may be headed in the years to come. Full article

(This article belongs to the Special Issue Personalized Medicine in Oncology)

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17 pages, 266 KiB

Open AccessReview

Imaging Biomarkers of Tumour Proliferation and Invasion for Personalised Lung Cancer Therapy

by Loredana G. Marcu

J. Pers. Med. 2020, 10(4), 222; https://doi.org/10.3390/jpm10040222 - 12 Nov 2020

Cited by 9 | Viewed by 2993

Abstract

Personalised treatment in oncology has seen great developments over the last decade, due to both technological advances and more in-depth knowledge of radiobiological processes occurring in tumours. Lung cancer therapy is no exception, as new molecular targets have been identified to further increase treatment specificity and sensitivity. Yet, tumour resistance to treatment is still one of the main reasons for treatment failure. This is due to a number of factors, among which tumour proliferation, the presence of cancer stem cells and the metastatic potential of the primary tumour are key features that require better controlling to further improve cancer management in general, and lung cancer treatment in particular. Imaging biomarkers play a key role in the identification of biological particularities within tumours and therefore are an important component of treatment personalisation in radiotherapy. Imaging techniques such as PET, SPECT, MRI that employ tumour-specific biomarkers already play a critical role in patient stratification towards individualized treatment. The aim of the current paper is to describe the radiobiological challenges of lung cancer treatment in relation to the latest imaging biomarkers that can aid in the identification of hostile cellular features for further treatment adaptation and tailoring to the individual patient’s needs. Full article

(This article belongs to the Special Issue Personalized Medicine in Oncology)

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14 pages, 1470 KiB

Open AccessReview

Patient-Derived Tumor Xenograft Models: Toward the Establishment of Precision Cancer Medicine

by Taichiro Goto

J. Pers. Med. 2020, 10(3), 64; https://doi.org/10.3390/jpm10030064 - 18 Jul 2020

Cited by 45 | Viewed by 10070

Abstract

Patient-derived xenografts (PDXs) describe models involving the implantation of patient-derived tumor tissue into immunodeficient mice. Compared with conventional preclinical models involving the implantation of cancer cell lines into mice, PDXs can be characterized by the preservation of tumor heterogeneity, and the tumor microenvironment (including stroma/vasculature) more closely resembles that in patients. Consequently, the use of PDX models has improved the predictability of clinical therapeutic responses to 80% or greater, compared with approximately 5% for existing models. In the future, molecular biological analyses, omics analyses, and other experiments will be conducted using recently prepared PDX models under the strong expectation that the analysis of cancer pathophysiology, stem cells, and novel treatment targets and biomarkers will be improved, thereby promoting drug development. This review outlines the methods for preparing PDX models, advances in cancer research using PDX mice, and perspectives for the establishment of precision cancer medicine within the framework of personalized cancer medicine. Full article

(This article belongs to the Special Issue Personalized Medicine in Oncology)

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Other

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10 pages, 910 KiB

Open AccessCommentary

Germline Mutations in Other Homologous Recombination Repair-Related Genes Than BRCA1/2: Predictive or Prognostic Factors?

by Laura Cortesi, Claudia Piombino and Angela Toss

J. Pers. Med. 2021, 11(4), 245; https://doi.org/10.3390/jpm11040245 - 28 Mar 2021

Cited by 20 | Viewed by 3521

Abstract

The homologous recombination repair (HRR) pathway repairs double-strand DNA breaks, mostly by BRCA1 and BRCA2, although other proteins such as ATM, CHEK2, and PALB2 are also involved. BRCA1/2 germline mutations are targeted by PARP inhibitors. The aim of this commentary is to explore whether germline mutations in HRR-related genes other than BRCA1/2 have to be considered as prognostic factors or predictive to therapies by discussing the results of two articles published in December 2020. The TBCRC 048 trial published by Tung et al. showed an impressive objective response rate to olaparib in metastatic breast cancer patients with germline PALB2 mutation compared to germline ATM and CHEK2 mutation carriers. Additionally, Yadav et al. observed a significantly longer overall survival in pancreatic adenocarcinoma patients with germline HRR mutations compared to non-carriers. In our opinion, assuming that PALB2 is a high-penetrant gene with a key role in the HRR system, PALB2 mutations are predictive factors for response to treatment. Moreover, germline mutations in the ATM gene provide a better outcome in pancreatic adenocarcinoma, being more often associated to wild-type KRAS. In conclusion, sequencing of HRR-related genes other than BRCA1/2 should be routinely offered as part of a biological characterization of pancreatic and breast cancers. Full article

(This article belongs to the Special Issue Personalized Medicine in Oncology)

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