DSpace Collection:https://hdl.handle.net/10171/520142024-03-29T12:04:18Z2024-03-29T12:04:18ZSignature-driven repurposing of Midostaurin for combination with MEK1/2 and KRASG12C inhibitors in lung cancerhttps://hdl.handle.net/10171/680952023-12-25T06:04:33Z2023-01-01T00:00:00ZTitle: Signature-driven repurposing of Midostaurin for combination with MEK1/2 and KRASG12C inhibitors in lung cancer
Abstract: Drug combinations are key to circumvent resistance mechanisms compromising response to single anti-cancer targeted therapies. The implementation of combinatorial approaches involving MEK1/2 or KRASG12C inhibitors in the context of KRAS-mutated lung cancers focuses fundamentally on targeting KRAS proximal activators or effectors. However, the antitumor effect is highly determined by compensatory mechanisms arising in defined cell types or tumor subgroups. A potential strategy to find drug combinations targeting a larger fraction of KRAS-mutated lung cancers may capitalize on the common, distal gene expression output elicited by oncogenic KRAS. By integrating a signature-driven drug repurposing approach with a pairwise pharmacological screen, here we show synergistic drug combinations consisting of multi-tyrosine kinase PKC inhibitors together with MEK1/2 or KRASG12C inhibitors. Such combinations elicit a cytotoxic response in both in vitro and in vivo models, which in part involves inhibition of the PKC inhibitor target AURKB. Proteome profiling links dysregulation of MYC expression to the effect of both PKC inhibitor-based drug combinations. Furthermore, MYC overexpression appears as a resistance mechanism to MEK1/2 and KRASG12C inhibitors. Our study provides a rational framework for selecting drugs entering combinatorial strategies and unveils MEK1/2- and KRASG12C-based therapies for lung cancer.2023-01-01T00:00:00ZDose volume histogram constraints in patients with soft tissue sarcomas of the extremities and the superficial trunk treated with surgery and perioperative HDR brachytherapyhttps://hdl.handle.net/10171/676752023-10-23T05:14:20Z2022-01-01T00:00:00ZTitle: Dose volume histogram constraints in patients with soft tissue sarcomas of the extremities and the superficial trunk treated with surgery and perioperative HDR brachytherapy
Abstract: Background: Wound healing complications (WHC), osteoradionecrosis (ORN), and nerve damage (ND) are
common adverse effects in adult patients with soft tissue sarcomas of the extremities and the superficial
trunk treated with surgery and perioperative high dose rate brachytherapy (PHDRB) alone or combined
with external beam radiotherapy (EBRT).
Rationale: Analysis of the treatment factors contributing to these complications can potentially minimize
their occurrence and severity.
Patients: A total of 169 patients enrolled in two parallel prospective studies were included in this analysis. Previously Unirradiated cases (Group 1; n = 139) were treated with surgical resection, 16–24 Gy of
PHDRB and 45 Gy of EBRT. Adjuvant chemotherapy was given to selected patients with high-grade
tumors. Previously irradiated cases (Group 2; n = 30) were treated with surgical resection and 32–
40 Gy of PHDRB without further EBRT.
Methods: Patient factors, tumor factors, surgical factors, PHDRB factors and EBRT factors were analyzed
using Cox univariate and multivariate analysis.
Results: In Previously Unirradiated cases, WHC, ORN and ND occurred in 38.8%, 5.0% and 19.4%.
Multivariate analysis indicated that WHC increased with CTV size (p = 0.02) and CTV2cm3 Physical dose
(p = 0.02). ORN increased with Bone2cm3 EQD2 67 Gy (p = 0.01) and ND was more frequent in patients
with TV100 DVH-based dose (tissue volume encompassed by the 100% isodose) 84 Gy (p < 0.01). In
Previously Irradiated cases, WHC, ORN and ND occurred in 63.3%, 3.3% and 23.3%. Multivariate analysis
showed that WHC was more frequent in patients with Skin2cm3 Lifetime EQD2 84 Gy (p = 0.01) and
ND was more frequent after CTVD90 Physical Doses 40 Gy (p < 0.01).
Conclusions: WHC in Previously Unirradiated patients can be minimized by using a more conservative
CTV definition together with a meticulous implant technique and planning aimed to minimize hyperdose
CTV2cm3 areas. In Previously Irradiated patients WHC may be mimimized considering Lifetime EQD2
Skin2cm3 doses. ORN can be reduced by using the Bone2cm3 EQD2 constraint. ND occurs more frequently
in patients with large tumors receiving high treated volume doses, but no specific constraints can be recommended due to the lack of peripheral nerve definition during brachytherapy planning.2022-01-01T00:00:00ZThe role of complement in tumorshttps://hdl.handle.net/10171/667682023-07-10T05:17:27Z2020-01-01T00:00:00ZTitle: The role of complement in tumors
Abstract: Activation of the complement system is one of the earliest responses to invading pathogens and
tissue damage (1). Complement activation leads to production of a range of effectors including the
opsonin C3b, the anaphylatoxins C3a and C5a, and the C5b-9 complex (membrane attack complex;
MAC) (2, 3). In addition to potent innate immune activities, complement effector systems also
contribute to efficient adaptive immune responses (4). While critical to proper immune function,
inappropriate or excessive complement activation contributes to many pathological inflammatory
conditions (5), including cancer. As described in this issue, the complement system is increasingly
recognized as a double-edged sword: on the one hand contributing to the anti-tumor response, but
on the other protecting the tumor against immune attack and promoting metastasis.2020-01-01T00:00:00ZId1 and PD-1 Combined Blockade Impairs Tumor Growth and Survival of KRAS-mutant Lung Cancer by Stimulating PD-L1 Expression and Tumor Infiltrating CD8+ T Cellshttps://hdl.handle.net/10171/663342024-03-27T08:51:28Z2020-01-01T00:00:00ZTitle: Id1 and PD-1 Combined Blockade Impairs Tumor Growth and Survival of KRAS-mutant Lung Cancer by Stimulating PD-L1 Expression and Tumor Infiltrating CD8+ T Cells
Abstract: The use of PD-1/PD-L1 checkpoint inhibitors in advanced NSCLC is associated with
longer survival. However, many patients do not benefit from PD-1/PD-L1 blockade, largely because
of immunosuppression. New immunotherapy-based combinations are under investigation in an
attempt to improve outcomes. Id1 (inhibitor of differentiation 1) is involved in immunosuppression. In this study, we explored the potential synergistic effect of the combination of Id1 inhibition
and pharmacological PD-L1 blockade in three different syngeneic murine KRAS-mutant lung
adenocarcinoma models. TCGA analysis demonstrated a negative and statistically significant
correlation between PD-L1 and Id1 expression levels. This observation was confirmed in vitro
in human and murine KRAS-driven lung cancer cell lines. In vivo experiments in KRAS-mutant
syngeneic and metastatic murine lung adenocarcinoma models showed that the combined blockade
targeting Id1 and PD-1 was more effective than each treatment alone in terms of tumor growth
impairment and overall survival improvement. Mechanistically, multiplex quantification of
CD3+/CD4+/CD8+ T cells and flow cytometry analysis showed that combined therapy favors tumor
infiltration by CD8+ T cells, whilst in vivo CD8+ T cell depletion led to tumor growth restoration.
Co-culture assays using CD8+ cells and tumor cells showed that T cells present a higher antitumor
effect when tumor cells lack Id1 expression. These findings highlight that Id1 blockade may contribute
to a significant immune enhancement of antitumor efficacy of PD-1 inhibitors by increasing PD-L1
expression and harnessing tumor infiltration of CD8+ T lymphocytes.2020-01-01T00:00:00Z