International Journal of Molecular Sciences

Research

19 pages, 4348 KiB

Open AccessArticle

Ceritinib-Induced Regression of an Insulin-Like Growth Factor-Driven Neuroepithelial Brain Tumor

by Alexandra Russo, Claudia Paret, Francesca Alt, Jürgen Burhenne, Margaux Fresnais, Wolfgang Wagner, Martin Glaser, Hannah Bender, Sabrina Huprich, Patrick N. Harter, Katharina Filipski, Nadine Lehmann, Nora Backes, Lea Roth, Larissa Seidmann, Clemens Sommer, Marc A. Brockmann, Torsten Pietsch, Marie A. Neu, Arthur Wingerter and Jörg Faber Show full author list Hide full author list

Int. J. Mol. Sci. 2019, 20(17), 4267; https://doi.org/10.3390/ijms20174267 - 30 Aug 2019

Cited by 11 | Viewed by 4372

Abstract

The insulin-like growth factor (IGF) pathway plays an important role in several brain tumor entities. However, the lack of inhibitors crossing the blood–brain barrier remains a significant obstacle for clinical translation. Here, we targeted the IGF pathway using ceritinib, an off-target inhibitor of [...] Read more.

The insulin-like growth factor (IGF) pathway plays an important role in several brain tumor entities. However, the lack of inhibitors crossing the blood–brain barrier remains a significant obstacle for clinical translation. Here, we targeted the IGF pathway using ceritinib, an off-target inhibitor of the IGF1 receptor (IGF1R) and insulin receptor (INSR), in a pediatric patient with an unclassified brain tumor and a notch receptor 1 (NOTCH1) germline mutation. Pathway analysis of the tumor revealed activation of the sonic hedgehog (SHH), the wingless and integrated-1 (WNT), the IGF, and the Notch pathway. The proliferation of the patient tumor cells (225ZL) was inhibited by arsenic trioxide (ATO), which is an inhibitor of the SHH pathway, by linsitinib, which is an inhibitor of IGF1R and INSR, and by ceritinib. 225ZL expressed INSR but not IGF1R at the protein level, and ceritinib blocked the phosphorylation of INSR. Our first personalized treatment included ATO, but because of side effects, we switched to ceritinib. After 46 days, we achieved a concentration of 1.70 µM of ceritinib in the plasma, and after 58 days, MRI confirmed that there was a response to the treatment. Ceritinib accumulated in the tumor at a concentration of 2.72 µM. Our data suggest ceritinib as a promising drug for the treatment of IGF-driven brain tumors. Full article

(This article belongs to the Special Issue Advances in the Comprehension of the Molecular Basis of Cancer and New Therapeutic Strategies)

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14 pages, 1747 KiB

Open AccessArticle

IGF1R Is a Potential New Therapeutic Target for HGNET-BCOR Brain Tumor Patients

by Nadine Vewinger, Sabrina Huprich, Larissa Seidmann, Alexandra Russo, Francesca Alt, Hannah Bender, Clemens Sommer, David Samuel, Nadine Lehmann, Nora Backes, Lea Roth, Patrick N. Harter, Katharina Filipski, Jörg Faber and Claudia Paret

Int. J. Mol. Sci. 2019, 20(12), 3027; https://doi.org/10.3390/ijms20123027 - 21 Jun 2019

Cited by 18 | Viewed by 4177

Abstract

(1) Background: The high-grade neuroepithelial tumor of the central nervous system with BCOR alteration (HGNET-BCOR) is a highly malignant tumor. Preclinical models and molecular targets are urgently required for this cancer. Previous data suggest a potential role of insulin-like growth factor (IGF) signaling [...] Read more.

(1) Background: The high-grade neuroepithelial tumor of the central nervous system with BCOR alteration (HGNET-BCOR) is a highly malignant tumor. Preclinical models and molecular targets are urgently required for this cancer. Previous data suggest a potential role of insulin-like growth factor (IGF) signaling in HGNET-BCOR. (2) Methods: The primary HGNET-BCOR cells PhKh1 were characterized by western blot, copy number variation, and methylation analysis and by electron microscopy. The expression of IGF2 and IGF1R was assessed by qRT-PCR. The effect of chemotherapeutics and IGF1R inhibitors on PhKh1 proliferation was tested. The phosphorylation of IGF1R and downstream molecules was assessed by western blot. (3) Results: Phkh1 cells showed a DNA methylation profile compatible with the DNA methylation class “HGNET-BCOR” and morphologic features of cellular cannibalism. IGF2 and IGF1R were highly expressed by three HGNET-BCOR tumor samples and PhKh1 cells. PhKh1 cells were particularly sensitive to vincristine, vinblastine, actinomycin D (IC₅₀ < 10 nM for all drugs), and ceritinib (IC₅₀ = 310 nM). Ceritinib was able to abrogate the proliferation of PhKh1 cells and blocked the phosphorylation of IGF1R and AKT. (4) Conclusion: IGF1R is as an attractive target for the development of new therapy protocols for HGNET-BCOR patients, which may include ceritinib and vinblastine. Full article

(This article belongs to the Special Issue Advances in the Comprehension of the Molecular Basis of Cancer and New Therapeutic Strategies)

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18 pages, 4697 KiB

Open AccessArticle

Active Fraction from Embryo Fish Extracts Induces Reversion of the Malignant Invasive Phenotype in Breast Cancer through Down-Regulation of TCTP and Modulation of E-cadherin/β-catenin Pathway

by Sara Proietti, Alessandra Cucina, Andrea Pensotti, Pier Mario Biava, Mirko Minini, Noemi Monti, Angela Catizone, Giulia Ricci, Erica Leonetti, Abdel Halim Harrath, Saleh H. Alwasel and Mariano Bizzarri

Int. J. Mol. Sci. 2019, 20(9), 2151; https://doi.org/10.3390/ijms20092151 - 30 Apr 2019

Cited by 20 | Viewed by 3756

Abstract

Some yet unidentified factors released by both oocyte and embryonic microenvironments demonstrated to be non-permissive for tumor development and display the remarkable ability to foster cell/tissue reprogramming, thus ultimately reversing the malignant phenotype. In the present study we observed how molecular factors extracted [...] Read more.

Some yet unidentified factors released by both oocyte and embryonic microenvironments demonstrated to be non-permissive for tumor development and display the remarkable ability to foster cell/tissue reprogramming, thus ultimately reversing the malignant phenotype. In the present study we observed how molecular factors extracted from Zebrafish embryos during specific developmental phases (20 somites) significantly antagonize proliferation of breast cancer cells, while reversing a number of prominent aspects of malignancy. Embryo extracts reduce cell proliferation, enhance apoptosis, and dramatically inhibit both invasiveness and migrating capabilities of cancer cells. Counteracting the invasive phenotype is a relevant issue in controlling tumor spreading and metastasis. Moreover, such effect is not limited to cancerous cells as embryo extracts were also effective in inhibiting migration and invasiveness displayed by normal breast cells undergoing epithelial–mesenchymal transition upon TGF-β1 stimulation. The reversion program involves the modulation of E-cadherin/β-catenin pathway, cytoskeleton remodeling with dramatic reduction in vinculin, as well as downregulation of TCTP and the concomitant increase in p53 levels. Our findings highlight that—contrary to the prevailing current “dogma”, which posits that neoplastic cells are irreversibly “committed”—the malignant phenotype can ultimately be “reversed”, at least partially, in response to environmental morphogenetic influences. Full article

(This article belongs to the Special Issue Advances in the Comprehension of the Molecular Basis of Cancer and New Therapeutic Strategies)

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23 pages, 10181 KiB

Open AccessArticle

Establishment and Characterization of 5-Fluorouracil-Resistant Human Colorectal Cancer Stem-Like Cells: Tumor Dynamics under Selection Pressure

by Maria Giovanna Francipane, Denis Bulanin and Eric Lagasse

Int. J. Mol. Sci. 2019, 20(8), 1817; https://doi.org/10.3390/ijms20081817 - 12 Apr 2019

Cited by 39 | Viewed by 5005

Abstract

5-Fluorouracil (5-FU) remains the gold standard of first-line treatment for colorectal cancer (CRC). Although it may initially debulk the tumor mass, relapses frequently occur, indicating the existence of cancer cells that are therapy-resistant and are capable of refueling tumor growth. To identify mechanisms [...] Read more.

5-Fluorouracil (5-FU) remains the gold standard of first-line treatment for colorectal cancer (CRC). Although it may initially debulk the tumor mass, relapses frequently occur, indicating the existence of cancer cells that are therapy-resistant and are capable of refueling tumor growth. To identify mechanisms of drug resistance, CRC stem-like cells were subjected to long-term 5-FU selection using either intermittent treatment regimen with the IC50 drug dose or continuous treatment regimen with escalating drug doses. Parental cancer cells were cultivated in parallel. Real-time PCR arrays and bioinformatic tools were used to investigate gene expression changes. We found the first method selected for cancer cells with more aggressive features. We therefore transplanted these cancer cells or parental cells in mice, and again, found that not only did the 5-FU-selected cancer cells generate more aggressive tumors with respect to their parental counterpart, but they also showed a different gene expression pattern as compared to what we had observed in vitro, with ID1 the top upregulated gene. We propose ID1 as a stemness marker pervasively expressed in secondary lesions emerging after completion of chemotherapy. Full article

(This article belongs to the Special Issue Advances in the Comprehension of the Molecular Basis of Cancer and New Therapeutic Strategies)

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25 pages, 2866 KiB

Open AccessArticle

Comparable Genomic Copy Number Aberrations Differ across Astrocytoma Malignancy Grades

by Nives Pećina-Šlaus, Anja Kafka, Kristina Gotovac Jerčić, Monika Logara, Anja Bukovac, Robert Bakarić and Fran Borovečki

Int. J. Mol. Sci. 2019, 20(5), 1251; https://doi.org/10.3390/ijms20051251 - 12 Mar 2019

Cited by 14 | Viewed by 4812

Abstract

A collection of intracranial astrocytomas of different malignancy grades was analyzed for copy number aberrations (CNA) in order to identify regions that are driving cancer pathogenesis. Astrocytomas were analyzed by Array Comparative Genomic Hybridization (aCGH) and bioinformatics utilizing a Bioconductor package, Genomic Identification [...] Read more.

A collection of intracranial astrocytomas of different malignancy grades was analyzed for copy number aberrations (CNA) in order to identify regions that are driving cancer pathogenesis. Astrocytomas were analyzed by Array Comparative Genomic Hybridization (aCGH) and bioinformatics utilizing a Bioconductor package, Genomic Identification of Significant Targets in Cancer (GISTIC) 2.0.23 and DAVID software. Altogether, 1438 CNA were found of which losses prevailed. On our total sample, significant deletions affected 14 chromosomal regions, out of which deletions at 17p13.2, 9p21.3, 13q12.11, 22q12.3 remained significant even at 0.05 q-value. When divided into malignancy groups, the regions identified as significantly deleted in high grades were: 9p21.3; 17p13.2; 10q24.2; 14q21.3; 1p36.11 and 13q12.11, while amplified were: 3q28; 12q13.3 and 21q22.3. Low grades comprised significant deletions at 3p14.3; 11p15.4; 15q15.1; 16q22.1; 20q11.22 and 22q12.3 indicating their involvement in early stages of tumorigenesis. Significantly enriched pathways were: PI3K-Akt, Cytokine-cytokine receptor, the nucleotide-binding oligomerization domain (NOD)–like receptor, Jak-STAT, retinoic acid-inducible gene (RIG)-I-like receptor and Toll-like receptor pathways. HPV and herpex simplex infection and inflammation pathways were also represented. The present study brings new data to astrocytoma research amplifying the wide spectrum of changes that could help us identify the regions critical for tumorigenesis. Full article

(This article belongs to the Special Issue Advances in the Comprehension of the Molecular Basis of Cancer and New Therapeutic Strategies)

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11 pages, 1653 KiB

Open AccessArticle

Improved Anticancer Effect of Recombinant Protein izTRAIL Combined with Sorafenib and Peptide iRGD

by Roman Fadeev, Alexey Chekanov, Marina Solovieva, Olga Bezborodova, Elena Nemtsova, Nadezda Dolgikh, Irina Fadeeva, Anatoly Senotov, Margarita Kobyakova, Yana Evstratova, Raisa Yakubovskaya and Vladimir Akatov

Int. J. Mol. Sci. 2019, 20(3), 525; https://doi.org/10.3390/ijms20030525 - 27 Jan 2019

Cited by 24 | Viewed by 5818

Abstract

One of the main problems in oncology is the development of drugs that cause the death of cancer cells without damaging normal cells. Another key problem to be solved is to suppress the drug resistance of cancer cells. The third important issue is [...] Read more.

One of the main problems in oncology is the development of drugs that cause the death of cancer cells without damaging normal cells. Another key problem to be solved is to suppress the drug resistance of cancer cells. The third important issue is to provide effective penetration of drug molecules to cancer cells. TRAIL (TNFα-related apoptosis inducing ligand)/Apo2L is a highly selective anticancer agent. However, the recombinant TRAIL protein having high efficiency against cancer cells in vitro was not effective in clinical trials. Recently we have discovered an acquisition of TRAIL resistance by cancer cells in confluent cultures, which is apparently a manifestation of the general phenomenon of multicellular resistance. The aim of this study was to evaluate whether the anticancer effect of the recombinant protein TRAIL in vivo can be improved by the suppression of multicellular TRAIL-resistance using sorafenib and a tumor-penetrating peptide iRGD, c(CRGDKGPDC). The results testified a great increase in the resistance of human fibrosarcoma HT-1080 cells to izTRAIL both in confluent cultures and in spheroids. Sorafenib administered at nontoxic concentration effectively suppressed confluent- or spheroid-mediated TRAIL-resistance of HT-1080 cells in vitro. Sorafenib combined with iRGD significantly improved the anticancer effect of the recombinant protein izTRAIL in HT-1080 human fibrosarcoma grafts in BALB/c nude mice. Consistent with this finding, multicellular TRAIL-resistance may be a reason of inefficacy of izTRAIL alone in vivo. The anticancer effect of the recombinant protein izTRAIL in vivo may be improved in combination with sorafenib, an inhibitor of multicellular TRAIL resistance and iRGD, the tumor-penetrating peptide. Full article

(This article belongs to the Special Issue Advances in the Comprehension of the Molecular Basis of Cancer and New Therapeutic Strategies)

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Review

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21 pages, 808 KiB

Open AccessReview

Mechanisms of Metastatic Tumor Dormancy and Implications for Cancer Therapy

by Christiana M. Neophytou, Theodora-Christina Kyriakou and Panagiotis Papageorgis

Int. J. Mol. Sci. 2019, 20(24), 6158; https://doi.org/10.3390/ijms20246158 - 6 Dec 2019

Cited by 55 | Viewed by 7988

Abstract

Metastasis, a multistep process during which tumor cells disseminate to secondary organs, represents the main cause of death for cancer patients. Metastatic dormancy is a late stage during cancer progression, following extravasation of cells at a secondary site, where the metastatic cells stop [...] Read more.

Metastasis, a multistep process during which tumor cells disseminate to secondary organs, represents the main cause of death for cancer patients. Metastatic dormancy is a late stage during cancer progression, following extravasation of cells at a secondary site, where the metastatic cells stop proliferating but survive in a quiescent state. When the microenvironmental conditions are favorable, they re-initiate proliferation and colonize, sometimes years after treatment of the primary tumor. This phenomenon represents a major clinical obstacle in cancer patient care. In this review, we describe the current knowledge regarding the genetic or epigenetic mechanisms that are activated by cancer cells that either sustain tumor dormancy or promote escape from this inactive state. In addition, we focus on the role of the microenvironment with emphasis on the effects of extracellular matrix proteins and in factors implicated in regulating dormancy during colonization to the lungs, brain, and bone. Finally, we describe the opportunities and efforts being made for the development of novel therapeutic strategies to combat metastatic cancer, by targeting the dormancy stage. Full article

(This article belongs to the Special Issue Advances in the Comprehension of the Molecular Basis of Cancer and New Therapeutic Strategies)

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16 pages, 933 KiB

Open AccessReview

Understanding the Mechanisms of Resistance in EGFR-Positive NSCLC: From Tissue to Liquid Biopsy to Guide Treatment Strategy

by Marzia Del Re, Stefania Crucitta, Giulia Gianfilippo, Antonio Passaro, Iacopo Petrini, Giuliana Restante, Angela Michelucci, Stefano Fogli, Filippo de Marinis, Camillo Porta, Antonio Chella and Romano Danesi

Int. J. Mol. Sci. 2019, 20(16), 3951; https://doi.org/10.3390/ijms20163951 - 14 Aug 2019

Cited by 63 | Viewed by 7714

Abstract

Liquid biopsy has emerged as an alternative source of nucleic acids for the management of Epidermal Growth Factor Receptor (EGFR)-mutant non-Small Cell Lung Cancer (NSCLC). The use of circulating cell-free DNA (cfDNA) has been recently introduced in clinical practice, resulting in [...] Read more.

Liquid biopsy has emerged as an alternative source of nucleic acids for the management of Epidermal Growth Factor Receptor (EGFR)-mutant non-Small Cell Lung Cancer (NSCLC). The use of circulating cell-free DNA (cfDNA) has been recently introduced in clinical practice, resulting in the improvement of the identification of druggable EGFR mutations for the diagnosis and monitoring of response to targeted therapy. EGFR-dependent (T790M and C797S mutations) and independent (Mesenchymal Epithelial Transition [MET] gene amplification, Kirsten Rat Sarcoma [KRAS], Phosphatidyl-Inositol 4,5-bisphosphate 3-Kinase Catalytic subunit Alpha isoform [PI3KCA], and RAF murine sarcoma viral oncogene homolog B1 [BRAF] gene mutations) mechanisms of resistance to EGFR tyrosine kinase inhibitors (TKIs) have been evaluated in plasma samples from NSCLC patients using highly sensitive methods (i.e., digital droplet PCR, Next Generation Sequencing), allowing for the switch to other therapies. Therefore, liquid biopsy is a non-invasive method able to detect the molecular dynamic changes that occur under the pressure of treatment, and to capture tumor heterogeneity more efficiently than is allowed by tissue biopsy. This review addresses how liquid biopsy may be used to guide the choice of treatment strategy in EGFR-mutant NSCLC. Full article

(This article belongs to the Special Issue Advances in the Comprehension of the Molecular Basis of Cancer and New Therapeutic Strategies)

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15 pages, 1417 KiB

Open AccessReview

Sphingolipid/Ceramide Pathways and Autophagy in the Onset and Progression of Melanoma: Novel Therapeutic Targets and Opportunities

by Michele Lai, Veronica La Rocca, Rachele Amato, Giulia Freer and Mauro Pistello

Int. J. Mol. Sci. 2019, 20(14), 3436; https://doi.org/10.3390/ijms20143436 - 12 Jul 2019

Cited by 33 | Viewed by 5424

Abstract

Melanoma is a malignant tumor deriving from neoplastic transformation of melanocytes. The incidence of melanoma has increased dramatically over the last 50 years. It accounts for most cases of skin cancer deaths. Early diagnosis leads to remission in 90% of cases of melanoma; [...] Read more.

Melanoma is a malignant tumor deriving from neoplastic transformation of melanocytes. The incidence of melanoma has increased dramatically over the last 50 years. It accounts for most cases of skin cancer deaths. Early diagnosis leads to remission in 90% of cases of melanoma; conversely, for melanoma at more advanced stages, prognosis becomes more unfavorable also because dvanced melanoma is often resistant to pharmacological and radiological therapies due to genetic plasticity, presence of cancer stem cells that regenerate the tumor, and efficient elimination of drugs. This review illustrates the role of autophagy in tumor progression and resistance to therapy, focusing on molecular targets for future drugs. Full article

(This article belongs to the Special Issue Advances in the Comprehension of the Molecular Basis of Cancer and New Therapeutic Strategies)

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18 pages, 514 KiB

Open AccessReview

Autoimmune Endocrine Dysfunctions Associated with Cancer Immunotherapies

by Silvia Martina Ferrari, Poupak Fallahi, Giusy Elia, Francesca Ragusa, Ilaria Ruffilli, Armando Patrizio, Maria Rosaria Galdiero, Enke Baldini, Salvatore Ulisse, Gianni Marone and Alessandro Antonelli

Int. J. Mol. Sci. 2019, 20(10), 2560; https://doi.org/10.3390/ijms20102560 - 24 May 2019

Cited by 84 | Viewed by 7293

Abstract

Immune checkpoint inhibitors block the checkpoint molecules. Different types of cancer immune checkpoint inhibitors have been approved recently: CTLA-4 monoclonal antibodies (as ipilimumab); anti-PD-1 monoclonal antibodies (as pembrolizumab and nivolumab); and anti-PD-L1 monoclonal antibodies (as atezolizumab, avelumab, and durmalumab). We collect recent published [...] Read more.

Immune checkpoint inhibitors block the checkpoint molecules. Different types of cancer immune checkpoint inhibitors have been approved recently: CTLA-4 monoclonal antibodies (as ipilimumab); anti-PD-1 monoclonal antibodies (as pembrolizumab and nivolumab); and anti-PD-L1 monoclonal antibodies (as atezolizumab, avelumab, and durmalumab). We collect recent published results about autoimmune endocrine dysfunctions associated with cancer antibody immunotherapies. These agents cause a raised immune response leading to immune-related adverse events (irAEs), varying from mild to fatal, based on the organ system and severity. Immune-related endocrine toxicities are usually irreversible in 50% of cases, and include hypophysitis, thyroid dysfunctions, type 1 diabetes mellitus, and adrenal insufficiency. Anti-PD-1-antibodies are more frequently associated with thyroid dysfunctions (including painless thyroiditis, hypothyroidism, thyrotoxicosis, or thyroid storm), while the most frequent irAE related to anti-CTLA-4-antibodies is hypophysitis. The combination of anti-CTLA-4 and anti-PD-1 antibodies is associated with a 30% chance of irAEs. Symptoms and clinical signs vary depending on the target organ. IrAEs are usually managed by an oncological therapist, but in more challenging circumstances (i.e., for new onset insulin–dependent diabetes, hypoadrenalism, gonadal hormones dysfunctions, or durable hypophysitis) an endocrinologist is needed. Full article

(This article belongs to the Special Issue Advances in the Comprehension of the Molecular Basis of Cancer and New Therapeutic Strategies)

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15 pages, 778 KiB

Open AccessReview

Understanding Immune Evasion and Therapeutic Targeting Associated with PD-1/PD-L1 Pathway in Diffuse Large B-cell Lymphoma

by Moo-Kon Song, Byeong-Bae Park and Jieun Uhm

Int. J. Mol. Sci. 2019, 20(6), 1326; https://doi.org/10.3390/ijms20061326 - 15 Mar 2019

Cited by 54 | Viewed by 8945

Abstract

In tumor microenvironment, the programmed death 1 (PD-1) immune checkpoint has a crucial role of mechanism of T cell exhaustion leading to tumor evasion. Ligands of PD-1, programmed death ligand 1/2 (PD-L1/L2) are over-expressed in tumor cells and participate in prolonged tumor progression [...] Read more.

In tumor microenvironment, the programmed death 1 (PD-1) immune checkpoint has a crucial role of mechanism of T cell exhaustion leading to tumor evasion. Ligands of PD-1, programmed death ligand 1/2 (PD-L1/L2) are over-expressed in tumor cells and participate in prolonged tumor progression and survivals. Recently, clinical trials for patients who failed to obtain an optimal response prior to standardized chemotherapy in several solid cancers have been focused on targeting therapy against PD-1 to reduce disease progression rates and prolonged survivals. Since various inhibitors targeting the immune checkpoint in PD-1/PD-L1 pathway in solid cancers have been introduced, promising approach using anti-PD-1 antibodies were attempted in several types of hematologic malignances. In diffuse large B cell lymphoma (DLBCL) as the most common and aggressive B cell type of non-Hodgkin’s lymphoma, anti-PD-1 and anti-PD-L1 antibodies were studies in various clinical trials. In this review, we summarized the results of several studies associated with PD-1/PD-L1 pathway as an immune evasion mechanism and described clinical trials about targeting therapy against PD-1/PD-L1 pathway in DLBCL. Full article

(This article belongs to the Special Issue Advances in the Comprehension of the Molecular Basis of Cancer and New Therapeutic Strategies)

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19 pages, 292 KiB

Open AccessCase Report

Treatment of Metastatic or High-Risk Solid Cancer Patients by Targeting the Immune System and/or Tumor Burden: Six Cases Reports

by Andrea Nicolini, Paola Ferrari, Riccardo Morganti and Angelo Carpi

Int. J. Mol. Sci. 2019, 20(23), 5986; https://doi.org/10.3390/ijms20235986 - 28 Nov 2019

Cited by 5 | Viewed by 3132

Abstract

This article summarizes the histories of six patients with different solid tumors treated with a new strategy based on tumor burden reduction and immune evasion as potential targets. All six patients were at a high risk of relapse and were likely to have [...] Read more.

This article summarizes the histories of six patients with different solid tumors treated with a new strategy based on tumor burden reduction and immune evasion as potential targets. All six patients were at a high risk of relapse and were likely to have a minimal residual disease following conventional therapy: biochemical recurrence (BCR) following radical prostatectomy (RP) (two prostate cancers patients), removal of distant metastases (one colorectal and one breast cancer), and complete response (CR) of distant metastases to conventional therapy (one breast cancer and one esophageal–gastric junction cancer). Four of the patients, two after RP and BCR, one after removal of a single pulmonary metastasis from breast cancer, and one after CR to chemotherapy of peritoneal metastases and ascites from an esophageal–gastric junction primary cancer, regularly received cycles of a new drug schedule with the aim of inhibiting immune suppression (IT). In these four patients, preliminary laboratory tests of peripheral blood suggested an interleukin (IL)-2/IL-12 mediated stimulation of cellular immune response with a concomitant decrease in vascular endothelial growth factor (VEGF) immune suppression. The fifth case was a breast cancer patient with distant metastases in CR, while receiving beta-interferon and interleukin-2 in addition to conventional hormone therapy. To date, all five patients are alive and doing well and they have been unexpectedly disease-free for 201 and 78 months following BCR, 28 months following the removal of a single pulmonary metastases, 32 months following CR to chemotherapy of peritoneal metastases and ascites, and 140 months following diagnosis of multiple bone metastases, respectively. The sixth patient, who had colorectal cancer and multiple synchronous liver metastases and underwent nine surgical interventions for metastatic disease, although not disease-free, is doing well 98 months after primary surgery. Our six cases reports can be interpreted with the hypothesis that immune manipulation and/or a concomitant low tumor burden favored their clinical outcome. Full article

(This article belongs to the Special Issue Advances in the Comprehension of the Molecular Basis of Cancer and New Therapeutic Strategies)

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