Biology subjects

Allevato, M. M.

Publications and source records attributed to Allevato, M. M..

4 recordsLinked to original sources

bioRxiv2026

Orthogonally targeted tumor radiosensitization using cell penetrating peptide-ATM inhibitor conjugates to stimulate anti-tumor immune responses

Tumor resistance to radiotherapy continues to be a significant problem in improving cancer patient outcomes. To overcome radioresistance, drugs that sensitize cancer cells to ionizing radiation have been tested. In theory, radiosensitizers should increase irradiated tumor kill and improve patient outcomes. In practice, the clinical utility of such drugs is curtailed by radiosensitization of peri-tumoral normal tissues causing toxicities. To address these issues, we developed an activatable cell penetrating peptide-drug conjugate to deliver a small molecule radiosensitizer with spatial precision to tumors. The activatable cell penetrating peptide (ACPP) scaffold cloaks a cell penetrating peptide-drug conjugate until it is unmasked within tumors through matrix metalloproteinase cleavage. Using antibody-drug conjugate linker chemistry, we attached the potent ataxia-telangiectasia mutated (ATM) kinase inhibitor AZD0156 to ACPP and created ACPP-AZD0156. In immune-competent murine cancer models, tumor-targeted ACPP-AZD0156 in combination with ionizing radiation stimulated tumor immune infiltration by CD8+ T cells and increased tumor control when compared to non-targeted ATM inhibitor. Mechanistically, ACPP-AZD0156 radiosensitized tumor control was dependent on the adaptive arm of the immune system. Finally, the combination of radiotherapy and ACPP-AZD0156 potentiated immune checkpoint inhibitors that resulted in durable tumor control. The therapeutic synergies of ACPP targeted ATM inhibitor to radiosensitize and stimulate anti-tumor immune responses provides a rationale for developing tumor-targeted radiosensitizer drug conjugates that restrict radiosensitization to cancer cells that then engages anti-tumor immune responses to improve cancer patient outcomes.

pharmacology and toxicology↗

bioRxiv2023

A kinome-wide synthetic lethal CRISPR/Cas9 screen reveals that mTOR inhibition prevents adaptive resistance to CDK4/CDK6 blockade in HNSCC

The comprehensive genomic analysis of the head and neck cancer (HNSCC) oncogenome revealed frequent loss of p16INK4A (CDKN2A) in most HPV negative HNSCC lesions, often concomitant with amplification of the cyclin D1 (CCND1) gene locus. However, cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors as single agents have shown modest effect in the clinic, even when combined with cetuximab. The aberrant activation of PI3K/mTOR pathway is highly prevalent in HNSCC, and recent clinical trials targeting mTOR showed promising results in terms of objective responses and progression free survival. However, the clinical efficacy of mTOR inhibitors (mTORi) for advanced HNSCC patients may be limited due to intrinsic or acquired resistance. By a kinome-wide CRISPR/Cas9 screen, we identified cell cycle inhibition as a synthetic lethal target for mTORi. Combination of mTORi and palbociclib, a CDK4/6 specific inhibitor, showed strong synergism in HNSCC-derived cells in vitro and in vivo. Remarkably, we found that adaptive increase in cyclin E1 (CCNE1) expression upon palbociclib treatment underlies the rapid acquired resistance to this CDK4/6 inhibitor in HNSCC. Mechanistically, mTORi inhibits the formation of eIF4G-CCNE1 mRNA complexes, with the consequent reduction in mRNA translation and CCNE1 protein expression. Our findings suggest that concomitant mTOR blockade reverts the adaptive resistance to palbociclib, thereby providing a novel multimodal therapeutic option for HNSCC patients by co-targeting mTOR and CDK4/6. Our findings may have broad implications to halt the emergence of palbociclib resistance.

cancer biology↗

bioRxiv2022

Lymphatic-Preserving Treatment Sequencing with Immune Checkpoint Inhibition Unleashes cDC1-Dependent Antitumor Immunity in HNSCC

Immune checkpoint inhibition (ICI) with anti-CTLA-4 and anti-PD-1 has revolutionized oncology; however, response rates remain limited in most cancer types, highlighting the need for more effective immune oncology (IO) treatment strategies. Paradoxically, head and neck squamous cell carcinoma (HNSCC), which bears a mutational burden and immune infiltrate commensurate with cancers that respond robustly to ICI, has demonstrated no response to anti- CTLA-4 in any setting or to anti-PD-1 for locally-advanced disease. Scrutiny of the landmark clinical trials defining current IO treatments in HNSCC reveals that recruited patients necessarily received regional ablative therapies per standard of care, prompting us to hypothesize that standard therapies, which by design ablate locoregional lymphatics, may compromise host immunity and the tumor response to ICI. To address this, we employed tobacco-signature HNSCC murine models in which we mapped tumor-draining lymphatics and developed models for regional lymphablation with surgery or radiation. Remarkably, we found that lymphablation eliminates the tumor ICI response, significantly worsening overall survival and repolarizing the tumor- and peripheral-immune compartments. Mechanistically, within tumor-draining lymphatics, we observed an upregulation of cDC1 cells and IFN-I signaling, showed that both are necessary for the ICI response and lost with lymphablation. Ultimately, we defined rational IO sequences that mobilize peripheral immunity, achieve optimal tumor responses, confer durable immunity and control regional lymphatic metastasis. In sum, we provide a mechanistic understanding of how standard regional, lymphablative therapies impact the response to ICI, which affords insights that can be applied to define rational, lymphatic-preserving IO treatment sequences for cancer. One Sentence SummaryDespite the promise of immune checkpoint inhibition, therapeutic responses remain limited, raising the possibility that standard of care treatments delivered in concert may compromise the tumor response; here, we provide a mechanistic understanding of how standard oncologic therapies targeting regional lymphatics impact the tumor response to immune-oncology therapy in order to define rational treatment sequences that mobilize systemic antitumor immunity, achieve optimal tumor responses, confer durable antitumor immunity, and control regional metastatic disease. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=107 SRC="FIGDIR/small/478744v1_ufig1.gif" ALT="Figure 1"> View larger version (33K): org.highwire.dtl.DTLVardef@542d71org.highwire.dtl.DTLVardef@737ad0org.highwire.dtl.DTLVardef@183f519org.highwire.dtl.DTLVardef@505ce2_HPS_FORMAT_FIGEXP M_FIG C_FIG

cancer biology↗

bioRxiv2019

Novel syngeneic animal model of tobacco-associated oral cancer reveals the activity of in situ anti-CTLA-4

Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer worldwide. Tobacco use is the main risk factor for HNSCC, and tobacco-associated HNSCCs have poor prognosis and response to available treatments. Recently approved anti-PD-1 immune checkpoint inhibitors showed limited activity ([≤]20%) in HNSCC, highlighting the need to identify new therapeutic options. For this, mouse models that accurately reflect the complexity of the HNSCC mutational landscape and tumor immune environment are urgently needed. Here, we report the first mouse HNSCC model system that recapitulates the human tobacco-related HNSCC mutanome, in which tumors grow when implanted in the tongue of immunocompetent mice. These HNSCC lesions have similar immune infiltration and response rates to anti-PD-1 ([≤]20%) immunotherapy as human HNSCCs. Remarkably, we found that >70% of HNSCC lesions respond to intratumoral anti-CTLA-4. This syngeneic HNSCC mouse model provides a platform for the development of novel immunotherapeutic options for HNSCC.

cancer biology↗