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Targeted Therapies in Colorectal Cancer: What’s New?

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A special issue of Cancers (ISSN 2072-6694). This special issue belongs to the section "Cancer Therapy".

Deadline for manuscript submissions: closed (31 October 2021) | Viewed by 41049

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Dr. Lisa Salvatore

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Comprehensive Cancer Center, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Roma, Italy.
Interests: colorectal cancer; pancreatic cancer; cholangiocarcinoma; target therapies; immunotherapy; clinical research; translational research; predictive and prognostic factors

Special Issue Information

We invite you to submit either an original research or a review article to this Special Issue on “Targeted Therapies in Colorectal Cancer: What’s New?”.

The personalization of treatment in colorectal cancer patients is one of the main challenges and progress in the selection of patients in order to optimize the use of old and new targeted therapies represents a current hot topic.

Hence, the purpose of this Special Issue of Cancers is to enhance knowledge regarding the latest progress—including clinical, translational, and preclinical—in the treatment of colorectal cancer with particular reference to target therapies used alone or in combination with chemotherapy, immunotherapy, and/or radiotherapy, especially in, but not limited to, specific subpopulations of colorectal cancer patients.

We encourage you to submit original research, short communications, systematic reviews, or meta-analyses as well as trials related to the latest progress on the theme topic.

Dr. Lisa Salvatore
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

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. Cancers is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

colorectal cancer
colon cancer
rectal cancer
targeted therapies
predictive markers

Published Papers (10 papers)

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Research

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13 pages, 1992 KiB

Open AccessArticle

Immune Response in Vitamin D Deficient Metastatic Colorectal Cancer Patients: A Player That Should Be Considered for Targeted Vitamin D Supplementation

by Cristina Morelli, Michela Rofei, Silvia Riondino, Daniela Fraboni, Francesco Torino, Augusto Orlandi, Manfredi Tesauro, Giovanna Del Vecchio Blanco, Massimo Federici, Hendrik-Tobias Arkenau, Vincenzo Formica and Mario Roselli

Cancers 2022, 14(11), 2594; https://doi.org/10.3390/cancers14112594 - 24 May 2022

Cited by 5 | Viewed by 1951

Abstract

Background: Vitamin D deficiency is a poor prognostic factor in metastatic colorectal cancer (mCRC); however, targeted supplementation trials have so far yielded limited results. We investigated clinical-laboratory parameters influencing vitamin D deficiency, with a particular focus on immune response, and the effect on survival. These parameters could help optimize targeted supplementation therapy. Methods: Association of plasma 25-hydroxyvitamin D (25(OH])D) with overall survival (OS) was assessed with the Hazard Ratio Smoothed Curve with Restricted Cubic Splines (HRSC-RCS) and maximally selected rank statistics (MSRS) in mCRC patients who underwent first-line chemotherapy. Several hematobiochemical variables were evaluated as predictors of vitamin D deficiency by means of Least Absolute Shrinkage and Selection Operator (LASSO) analysis. In a patient subset, peripheral lymphocyte subpopulations were also analyzed. Results: One hundred thirty-three mCRC patients were included. The median(m) baseline 25(OH)D was 10.8 ng/mL (range 3–53.4). HRSC-RCS revealed a linear association between 25(OH)D and OS. MSRS found 10 ng/mL as the optimal 25(OH)D cut-off. The median OS for 25(OH)D < 10 (n = 60) vs. > 10 ng/mL (n = 73) was 12.3 and 24.5 months, respectively (p = 0.002). The LASSO analysis identified high neutrophil-to-lymphocyte ratio (NLR > 3.5) as the strongest predictor of vitamin D deficiency (Odds Ratio 3.35, p 0.0009). Moreover, patients with low 25(OH)D levels (< 10 ng/mL) and high NLR (>3.5) had the shortest survival and patients with 25(OH)D >10 ng/mL and NLR <3.5 had the longest: mOS 8.1 and 28.1 months, respectively, HR 3.40 (1.76–6.59), p 0.0004. Besides the significant difference in NLR between 25(OH)D < and > 10 ng/mL patients (mNLR 3.6 vs. 2.9, p 0.03), the lymphocyte subpopulation analysis revealed that vitamin D deficiency was associated with high T- CD4+ (p = 0.04) and low B (p = 0.03) lymphocyte frequency. Conclusions: NLR is a powerful predictor of Vitamin D deficiency and can further help in stratifying prognosis. Vitamin D deficiency was associated with significant variations in peripheral immune cells. We hypothesize that integrated targeted interventions to both vitamin D and immune system would improve the prognosis of mCRC patients. Full article

(This article belongs to the Special Issue Targeted Therapies in Colorectal Cancer: What’s New?)

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16 pages, 1008 KiB

Open AccessArticle

Exact Primary Tumor Location in mCRC: Prognostic Value and Predictive Impact on Anti-EGFR mAb Efficacy

by Annabel H. S. Alig, Volker Heinemann, Michael Geissler, Ludwig Fischer von Weikersthal, Thomas Decker, Kathrin Heinrich, Swantje Held, Lena Weiss, Laura E. Fischer, Nicolas Moosmann, Arndt Stahler, Ivan Jelas, Annika Kurreck, Jobst C. von Einem, Anke C. Reinacher-Schick, Andrea Tannapfel, Clemens Giessen-Jung, Sebastian Stintzing and Dominik P. Modest

Cancers 2022, 14(3), 526; https://doi.org/10.3390/cancers14030526 - 21 Jan 2022

Cited by 2 | Viewed by 1656

Abstract

Primary tumor sidedness (left vs. right) has prognostic and predictive impact on anti-EGFR agent efficacy and thus management of metastatic colorectal cancer (mCRC). This analysis evaluates the relevance of primary tumor location (PTL) in RAS/BRAF wild-type mCRC patients, when dividing the colorectal frame into six segments. This pooled analysis, performed on a single-patient basis of five randomized first-line therapy trials, evaluates the impact of exact PTL classification on baseline characteristics, prognosis and prediction of anti-EGFR antibody efficacy by chi-square and log-rank tests, the Kaplan–Meier method, Cox and logistic regressions. The PTL was significantly associated with metastatic spread: liver (p = 0.001), lung (p = 0.047), peritoneal (p < 0.001) and lymph nodes (p = 0.048). A multivariate analysis indicated an impact on anti-EGFR agent efficacy in terms of overall survival depending on the exact primary tumor location: from detrimental in caecal (HR 2.63), rather neutral effects in the ascending colon (HR 1.24), right flexure/transverse colon (HR 0.99) and left flexure/descending colon (HR 0.91) to clear benefit in sigmoid (HR 0.71) and rectal (HR 0.58) primaries. Exact primary tumor location affects anti-EGFR antibody efficacy in a rather continuous than a dichotomous fashion in RAS/BRAF wild-type mCRC patients. This perspective might help to support clinical decisions when anti-EGFR antibodies are considered. Full article

(This article belongs to the Special Issue Targeted Therapies in Colorectal Cancer: What’s New?)

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22 pages, 2240 KiB

Open AccessArticle

Drug Repositioning Based on the Reversal of Gene Expression Signatures Identifies TOP2A as a Therapeutic Target for Rectal Cancer

by Robson Francisco Carvalho, Luisa Matos do Canto, Sarah Santiloni Cury, Torben Frøstrup Hansen, Lars Henrik Jensen and Silvia Regina Rogatto

Cancers 2021, 13(21), 5492; https://doi.org/10.3390/cancers13215492 - 31 Oct 2021

Cited by 14 | Viewed by 4471

Abstract

Rectal cancer is a common disease with high mortality rates and limited therapeutic options. Here we combined the gene expression signatures of rectal cancer patients with the reverse drug-induced gene-expression profiles to identify drug repositioning candidates for cancer therapy. Among the predicted repurposable drugs, topoisomerase II inhibitors (doxorubicin, teniposide, idarubicin, mitoxantrone, and epirubicin) presented a high potential to reverse rectal cancer gene expression signatures. We showed that these drugs effectively reduced the growth of colorectal cancer cell lines closely representing rectal cancer signatures. We also found a clear correlation between topoisomerase 2A (TOP2A) gene copy number or expression levels with the sensitivity to topoisomerase II inhibitors. Furthermore, CRISPR-Cas9 and shRNA screenings confirmed that loss-of-function of the TOP2A has the highest efficacy in reducing cellular proliferation. Finally, we observed significant TOP2A copy number gains and increased expression in independent cohorts of rectal cancer patients. These findings can be translated into clinical practice to evaluate TOP2A status for targeted and personalized therapies based on topoisomerase II inhibitors in rectal cancer patients. Full article

(This article belongs to the Special Issue Targeted Therapies in Colorectal Cancer: What’s New?)

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11 pages, 2392 KiB

Open AccessArticle

Statin Use and Long-Term Mortality after Rectal Cancer Surgery

by Arvid Pourlotfi, Gary Alan Bass, Rebecka Ahl Hulme, Maximilian Peter Forssten, Gabriel Sjolin, Yang Cao, Peter Matthiessen and Shahin Mohseni

Cancers 2021, 13(17), 4288; https://doi.org/10.3390/cancers13174288 - 25 Aug 2021

Cited by 3 | Viewed by 1618

Abstract

Background: The current study aimed to assess the association between regular statin therapy and postoperative long-term all-cause and cancer-specific mortality following curative surgery for rectal cancer. The hypothesis was that statin exposure would be associated with better survival. Methods: Patients with stage I–III rectal cancer undergoing surgical resection with curative intent were extracted from the nationwide, prospectively collected, Swedish Colorectal Cancer Register (SCRCR) for the period from January 2007 and October 2016. Patients were defined as having ongoing statin therapy if they had filled a statin prescription within 12 months before and after surgery. Cox proportional hazards models were employed to investigate the association between statin use and postoperative five-year all-cause and cancer-specific mortality. Results: The cohort consisted of 10,743 patients who underwent a surgical resection with curative intent for rectal cancer. Twenty-six percent (n = 2797) were classified as having ongoing statin therapy. Statin users had a considerably decreased risk of all-cause (adjusted hazard ratio (HR) 0.66, 95% confidence interval (CI): 0.60–0.73, p < 0.001) and cancer-specific (adjusted HR 0.60, 95% CI: 0.47–0.75, p < 0.001) mortality up to five years following surgery. Conclusions: Statin use was associated with a lower risk of both all-cause and rectal cancer-specific mortality following curative surgical resections for rectal cancer. The findings should be confirmed in future prospective clinical trials. Full article

(This article belongs to the Special Issue Targeted Therapies in Colorectal Cancer: What’s New?)

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16 pages, 2294 KiB

Open AccessArticle

Synthetic Lethality Screening Highlights Colorectal Cancer Vulnerability to Concomitant Blockade of NEDD8 and EGFR Pathways

by Federica Invrea, Simona Punzi, Consalvo Petti, Rosalba Minelli, Michael D. Peoples, Christopher A. Bristow, Valentina Vurchio, Alessia Corrado, Alberto Bragoni, Caterina Marchiò, Andrea Bertotti, Livio Trusolino, Alberto Bardelli, Claudio Isella, Alessandro Carugo, Giulio F. Draetta and Enzo Medico

Cancers 2021, 13(15), 3805; https://doi.org/10.3390/cancers13153805 - 28 Jul 2021

Cited by 6 | Viewed by 2686

Abstract

Colorectal cancer (CRC) is a heterogeneous disease showing significant variability in clinical aggressiveness. Primary and acquired resistance limits the efficacy of available treatments, and identification of effective drug combinations is needed to further improve patients’ outcomes. We previously found that the NEDD8-activating enzyme inhibitor pevonedistat induced tumor stabilization in preclinical models of poorly differentiated, clinically aggressive CRC resistant to available therapies. To identify drugs that can be effectively combined with pevonedistat, we performed a “drop-out” loss-of-function synthetic lethality screening with an shRNA library covering 200 drug-target genes in four different CRC cell lines. Multiple screening hits were found to be involved in the EGFR signaling pathway, suggesting that, rather than inhibition of a specific gene, interference with the EGFR pathway at any level could be effectively leveraged for combination therapies based on pevonedistat. Exploiting both BRAF-mutant and RAS/RAF wild-type CRC models, we validated the therapeutic relevance of our findings by showing that combined blockade of NEDD8 and EGFR pathways led to increased growth arrest and apoptosis both in vitro and in vivo. Pathway modulation analysis showed that compensatory feedback loops induced by single treatments were blunted by the combinations. These results unveil possible therapeutic opportunities in specific CRC clinical settings. Full article

(This article belongs to the Special Issue Targeted Therapies in Colorectal Cancer: What’s New?)

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Review

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17 pages, 749 KiB

Open AccessReview

Targeting the DNA Damage Response Pathway as a Novel Therapeutic Strategy in Colorectal Cancer

by Fabio Catalano, Roberto Borea, Silvia Puglisi, Andrea Boutros, Annalice Gandini, Malvina Cremante, Valentino Martelli, Stefania Sciallero and Alberto Puccini

Cancers 2022, 14(6), 1388; https://doi.org/10.3390/cancers14061388 - 09 Mar 2022

Cited by 22 | Viewed by 3479

Abstract

Major advances have been made in CRC treatment in recent years, especially in molecularly driven therapies and immunotherapy. Despite this, a large number of advanced colorectal cancer patients do not benefit from these treatments and their prognosis remains poor. The landscape of DNA damage response (DDR) alterations is emerging as a novel target for treatment in different cancer types. PARP inhibitors have been approved for the treatment of ovarian, breast, pancreatic, and prostate cancers carrying deleterious BRCA1/2 pathogenic variants or homologous recombination repair (HRR) deficiency (HRD). Recent research reported on the emerging role of HRD in CRC and showed that alterations in these genes, either germline or somatic, are carried by up to 15–20% of CRCs. However, the role of HRD is still widely unknown, and few data about their clinical impact are available, especially in CRC patients. In this review, we report preclinical and clinical data currently available on DDR inhibitors in CRC. We also emphasize the predictive role of DDR mutations in response to platinum-based chemotherapy and the potential clinical role of DDR inhibitors. More preclinical and clinical trials are required to better understand the impact of DDR alterations in CRC patients and the therapeutic opportunities with novel DDR inhibitors. Full article

(This article belongs to the Special Issue Targeted Therapies in Colorectal Cancer: What’s New?)

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21 pages, 357 KiB

Open AccessReview

Tackling Refractory Metastatic Colorectal Cancer: Future Perspectives

by Nicola Personeni, Valeria Smiroldo, Emilio Francesco Giunta, Maria Giuseppina Prete, Lorenza Rimassa, Giacomo Bregni and Francesco Sclafani

Cancers 2021, 13(18), 4506; https://doi.org/10.3390/cancers13184506 - 07 Sep 2021

Cited by 11 | Viewed by 2734

Abstract

Substantial improvements have characterized the systemic treatment of metastatic colorectal cancer (mCRC) over the past 20 years. Besides strong evidence that supports the use of RAS and BRAF status as prognostic and predictive indicators of disease and response, novel technologies have made possible the incorporation of emerging biomarkers for the management of mCRC. On one hand, the discovery of point mutations, amplifications, fusions, and gene expression profiles highlights the genomic and dynamic complexity of CRC. On the other, such discoveries are leading to newer biomarker-driven strategies that add to existing anti-epidermal growth factor receptor (EGFR) and anti-angiogenic approaches. In addition, the availability of a wide molecular profiling has relevant implications for patient prognosis and treatment benefits. Here, we will review the molecular underpinnings and clinical data supporting novel targeted treatments under development for refractory mCRC harboring BRAF mutations, KRAS G12C mutations, HER2 amplification, and less common molecular alterations, such as the re-arrangements of NTRK, ALK, and ROS1. Additionally, we will discuss novel strategies driving the rechallenge of EGFR antibodies and the incorporation of newer anti-angiogenic agents in the therapeutic armamentarium. Full article

(This article belongs to the Special Issue Targeted Therapies in Colorectal Cancer: What’s New?)

18 pages, 1427 KiB

Open AccessReview

Challenges of Neoantigen Targeting in Lynch Syndrome and Constitutional Mismatch Repair Deficiency Syndrome

by Asima Abidi, Mark A. J. Gorris, Evan Brennan, Marjolijn C. J. Jongmans, Dilys D. Weijers, Roland P. Kuiper, Richarda M. de Voer, Nicoline Hoogerbrugge, Gerty Schreibelt and I. Jolanda M. de Vries

Cancers 2021, 13(10), 2345; https://doi.org/10.3390/cancers13102345 - 13 May 2021

Cited by 4 | Viewed by 5124

Abstract

Lynch syndrome (LS) and constitutional mismatch repair deficiency (CMMRD) are hereditary disorders characterised by a highly increased risk of cancer development. This is due to germline aberrations in the mismatch repair (MMR) genes, which results in a high mutational load in tumours of these patients, including insertions and deletions in genes bearing microsatellites. This generates microsatellite instability and cause reading frameshifts in coding regions that could lead to the generation of neoantigens and opens up avenues for neoantigen targeting immune therapies prophylactically and therapeutically. However, major obstacles need to be overcome, such as the heterogeneity in tumour formation within and between LS and CMMRD patients, which results in considerable variability in the genes targeted by mutations, hence challenging the choice of suitable neoantigens. The machine-learning methods such as NetMHC and MHCflurry that predict neoantigen- human leukocyte antigen (HLA) binding affinity provide little information on other aspects of neoantigen presentation. Immune escape mechanisms that allow MMR-deficient cells to evade surveillance combined with the resistance to immune checkpoint therapy make the neoantigen targeting regimen challenging. Studies to delineate shared neoantigen profiles across patient cohorts, precise HLA binding algorithms, additional therapies to counter immune evasion and evaluation of biomarkers that predict the response of these patients to immune checkpoint therapy are warranted. Full article

(This article belongs to the Special Issue Targeted Therapies in Colorectal Cancer: What’s New?)

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17 pages, 1036 KiB

Open AccessFeature PaperReview

Targeting BRAF and RAS in Colorectal Cancer

by Helene Bellio, Jean David Fumet and Francois Ghiringhelli

Cancers 2021, 13(9), 2201; https://doi.org/10.3390/cancers13092201 - 03 May 2021

Cited by 28 | Viewed by 4630

Abstract

Colorectal cancer (CRC) is still one of the most frequent forms of cancer in the world in terms of incidence. Around 40% of CRC patients carry a mutation of the Kirsten rat sarcoma (KRAS) gene, while 10% have a mutation in the B-Raf proto-oncogene serine/threonine kinase (BRAF) gene. These mutations are responsible for dysregulation of the mitogen-associated protein kinase (MAPK) pathway, leading to the proliferation, differentiation, angiogenesis, and resistance to apoptosis of cells. Activation of the MAPK pathway results in adaptive therapeutic resistance, rendering EGFR inhibitors ineffective. This review aims to highlight the recent findings that have improved our understanding of KRAS and BRAF mutations in colorectal cancer and to describe new targeted therapies, used alone or in combination. Full article

(This article belongs to the Special Issue Targeted Therapies in Colorectal Cancer: What’s New?)

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Other

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14 pages, 1726 KiB

Open AccessSystematic Review

Immune-Checkpoint Inhibitors for Metastatic Colorectal Cancer: A Systematic Review of Clinical Outcomes

by Dmitrii Shek, Liia Akhuba, Matteo S. Carlino, Adnan Nagrial, Tania Moujaber, Scott A. Read, Bo Gao and Golo Ahlenstiel

Cancers 2021, 13(17), 4345; https://doi.org/10.3390/cancers13174345 - 27 Aug 2021

Cited by 14 | Viewed by 10940

Abstract

Background. Colorectal cancer (CRC) is the fourth most deadly cancer worldwide. Unfortunately, a quarter of the patients are diagnosed at late stages, when surgical options are limited. Targeted therapies, particularly immune-checkpoint inhibitors (ICIs), are the latest addition and have been studied herein regarding their efficacy outcomes. Methods. Clinical studies were identified through the PubMed, Scopus and Cochrane databases. Any trial that evaluated ICIs in patients with metastatic CRC (mCRC) and reported the objective response rate was deemed eligible. Data analysis was performed by employing the random-effects model in STATA v.17. Results. A total of 461 articles were identified; 13 clinical trials were included, encompassing a total cohort of 1209 patients. Our study determined that a single PD-1/PD-L1 checkpoint blockade provides durable clinical response in mCRC patients with high microsatellite instability (MSI-H). The combinatorial therapy of CTLA-4 + PD-1 inhibitors also showed high response rates in pre-treated MSI-H patients. The single-arm REGONIVO trial reported durable clinical response in patients with microsatellite stable (MSS) status. Conclusions. Our study surmises that PD-1/PD-L1 inhibitors as well as combination therapy with CTLA-4 and PD-1 inhibitors show encouraging response rates in mCRC patients, albeit exclusively in patients with cancer that are of MSI-H status. A single study suggests that nivolumab + regorafenib can reach a durable response rate in MSS patients; however, further studies in larger randomized settings are required. Full article

(This article belongs to the Special Issue Targeted Therapies in Colorectal Cancer: What’s New?)

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