Maryam Quraishi - Academia.edu (original) (raw)
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Papers by Maryam Quraishi
Biomaterials, Jul 1, 2020
This is a PDF file of an article that has undergone enhancements after acceptance, such as the ad... more This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Experimental and Molecular Therapeutics, Aug 13, 2020
Patients with locally advanced cancers are treated with combined radiotherapy and chemotherapy, h... more Patients with locally advanced cancers are treated with combined radiotherapy and chemotherapy, however curability is poor and side effects severe. Drugs that sensitize tumors to radiotherapy have been tried to improve cure, but tumor specificity remains a challenge. To achieve tumor selectivity of small molecule radiosensitizers, we tested as a strategy active tumor targeting utilizing peptide-based drug conjugates that split the responsibilities for targeting and radiosensitization into distinct molecular tasks. The tumor milieu possesses localizing beacons that can guide drug delivery using tumor cell surface receptors and microenvironment extracellular matrix metalloproteinases (MMPs). Here we applied peptide-based linkers to test for tumor selective drug delivery and radiosensitization by chemically conjugating the DNA damage checkpoint kinase 1/2 inhibitor AZD7762 to antibody to or cell penetrating peptides. AZD7762 governs DNA damage response and irradiated cell fate. We synthesized drug conjugates of AZD7762 and compared their anti-tumor efficacy in combination with ionizing radiation (IR). An antibody drug conjugate (ADC) was built by attaching AZD7762 to the anti-EGFR antibody cetuximab. Polycationic cell penetrating peptide drug conjugates were constructed by linking AZD7762 to a 9 amino acid repeat of D-arginine and keeping it bare (r9-AZD7762) or cloaking r9 within a MMP-2/9 triggered activatable cell penetrating peptide scaffold (ACPP-AZD7762). In contrast to receptor directed ADCs, ACPPs redirect extracellular tumor microenvironment proteases to guide drug delivery. Intact, ACPPs are charge neutral which blocks the conjugated drug from cell entry. Upon cleavage by tumor overexpressed MMPs, the ACPP scaffold releases drug conjugated polycationic peptide which is then internalized by cells. We found that while cetuximab-AZD7762 ADC had high affinity for EGFR overexpressing tumor cells and prolonged blood circulation in murine models, cetuximab-AZD7762 lacked anti-tumor efficacy. On the other extreme, naked r9-AZD7762 drug conjugate was indiscriminately cytotoxic and radiosensitized a panel of tumor cell lines in cell culture: CAL27, A549, PANC1 and HCT116. However, r9 cell penetrating peptides lacked tumor specificity when intravenously injected into mice. In contrast, MMP-2/9 sensitive ACPPs balanced tumor selectivity with drug efficacy. Intact, ACPPs held conjugated AZD7762 in a pro-drug inactive state that upon tumor microenvironment ACPP cleavage resulted in tumor selective drug accumulation and anti-tumor efficacy in combination with IR. Importantly, a control non-cleavable ACPP-AZD7762 did not improve tumor control with IR, demonstrating the necessity of ACPP cleavage to release active drug. These results highlight the utility of the ACPP technology platform to target amine containing radiosensitizing drugs to tumor tissues based on extracellular protease activity that overcome the limitations of ADC conjugated radiosensitizers. Citation Format: Dina V. Hingorani, Maria F. Camargo, Maryam A. Quraishi, Joseph Aguilera, Stephen R. Adams, Sunil J. Advani. Redirecting tumor extracellular proteases to target radiosensitizer delivery [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 6272.
Nature Communications
Locally advanced cancers remain therapeutically challenging to eradicate. The most successful tre... more Locally advanced cancers remain therapeutically challenging to eradicate. The most successful treatments continue to combine decades old non-targeted chemotherapies with radiotherapy that unfortunately increase normal tissue damage in the irradiated field and have systemic toxicities precluding further treatment intensification. Therefore, alternative molecularly guided systemic therapies are needed to improve patient outcomes when applied with radiotherapy. In this work, we report a trimodal precision cytotoxic chemo-radio-immunotherapy paradigm using spatially targeted auristatin warheads. Tumor-directed antibodies and peptides conjugated to radiosensitizing monomethyl auristatin E (MMAE) specifically produce CD8 T cell dependent durable tumor control of irradiated tumors and immunologic memory. In combination with ionizing radiation, MMAE sculpts the tumor immune infiltrate to potentiate immune checkpoint inhibition. Here, we report therapeutic synergies of targeted cytotoxic aur...
Pharmaceutics, 2021
Recent advances in immunotherapy have revolutionized cancer therapy. Immunotherapies can engage t... more Recent advances in immunotherapy have revolutionized cancer therapy. Immunotherapies can engage the adaptive and innate arms of the immune system. Therapeutics targeting immune checkpoint inhibitors (i.e., CTLA-4; PD-1, and PD-L1) have shown efficacy for subsets of cancer patients by unleashing an adaptive antitumor immune response. Alternatively, small molecule immune modulators of the innate immune system such as toll-like receptor (TLR) agonists are being developed for cancer therapy. TLRs function as pattern recognition receptors to microbial products and are also involved in carcinogenesis. Reisquimod is a TLR 7/8 agonist that has antitumor efficacy. However, systemic delivery free resiquimod has proven to be challenging due to toxicity of nonspecific TLR 7/8 activation. Therefore, we developed a targeted peptide-drug conjugate strategy for systemic delivery of resiquimod. We designed an activatable cell penetrating peptide to deliver resiquimod specifically to the tumor tissue...
Biomaterials, Jul 1, 2020
This is a PDF file of an article that has undergone enhancements after acceptance, such as the ad... more This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Experimental and Molecular Therapeutics, Aug 13, 2020
Patients with locally advanced cancers are treated with combined radiotherapy and chemotherapy, h... more Patients with locally advanced cancers are treated with combined radiotherapy and chemotherapy, however curability is poor and side effects severe. Drugs that sensitize tumors to radiotherapy have been tried to improve cure, but tumor specificity remains a challenge. To achieve tumor selectivity of small molecule radiosensitizers, we tested as a strategy active tumor targeting utilizing peptide-based drug conjugates that split the responsibilities for targeting and radiosensitization into distinct molecular tasks. The tumor milieu possesses localizing beacons that can guide drug delivery using tumor cell surface receptors and microenvironment extracellular matrix metalloproteinases (MMPs). Here we applied peptide-based linkers to test for tumor selective drug delivery and radiosensitization by chemically conjugating the DNA damage checkpoint kinase 1/2 inhibitor AZD7762 to antibody to or cell penetrating peptides. AZD7762 governs DNA damage response and irradiated cell fate. We synthesized drug conjugates of AZD7762 and compared their anti-tumor efficacy in combination with ionizing radiation (IR). An antibody drug conjugate (ADC) was built by attaching AZD7762 to the anti-EGFR antibody cetuximab. Polycationic cell penetrating peptide drug conjugates were constructed by linking AZD7762 to a 9 amino acid repeat of D-arginine and keeping it bare (r9-AZD7762) or cloaking r9 within a MMP-2/9 triggered activatable cell penetrating peptide scaffold (ACPP-AZD7762). In contrast to receptor directed ADCs, ACPPs redirect extracellular tumor microenvironment proteases to guide drug delivery. Intact, ACPPs are charge neutral which blocks the conjugated drug from cell entry. Upon cleavage by tumor overexpressed MMPs, the ACPP scaffold releases drug conjugated polycationic peptide which is then internalized by cells. We found that while cetuximab-AZD7762 ADC had high affinity for EGFR overexpressing tumor cells and prolonged blood circulation in murine models, cetuximab-AZD7762 lacked anti-tumor efficacy. On the other extreme, naked r9-AZD7762 drug conjugate was indiscriminately cytotoxic and radiosensitized a panel of tumor cell lines in cell culture: CAL27, A549, PANC1 and HCT116. However, r9 cell penetrating peptides lacked tumor specificity when intravenously injected into mice. In contrast, MMP-2/9 sensitive ACPPs balanced tumor selectivity with drug efficacy. Intact, ACPPs held conjugated AZD7762 in a pro-drug inactive state that upon tumor microenvironment ACPP cleavage resulted in tumor selective drug accumulation and anti-tumor efficacy in combination with IR. Importantly, a control non-cleavable ACPP-AZD7762 did not improve tumor control with IR, demonstrating the necessity of ACPP cleavage to release active drug. These results highlight the utility of the ACPP technology platform to target amine containing radiosensitizing drugs to tumor tissues based on extracellular protease activity that overcome the limitations of ADC conjugated radiosensitizers. Citation Format: Dina V. Hingorani, Maria F. Camargo, Maryam A. Quraishi, Joseph Aguilera, Stephen R. Adams, Sunil J. Advani. Redirecting tumor extracellular proteases to target radiosensitizer delivery [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 6272.
Nature Communications
Locally advanced cancers remain therapeutically challenging to eradicate. The most successful tre... more Locally advanced cancers remain therapeutically challenging to eradicate. The most successful treatments continue to combine decades old non-targeted chemotherapies with radiotherapy that unfortunately increase normal tissue damage in the irradiated field and have systemic toxicities precluding further treatment intensification. Therefore, alternative molecularly guided systemic therapies are needed to improve patient outcomes when applied with radiotherapy. In this work, we report a trimodal precision cytotoxic chemo-radio-immunotherapy paradigm using spatially targeted auristatin warheads. Tumor-directed antibodies and peptides conjugated to radiosensitizing monomethyl auristatin E (MMAE) specifically produce CD8 T cell dependent durable tumor control of irradiated tumors and immunologic memory. In combination with ionizing radiation, MMAE sculpts the tumor immune infiltrate to potentiate immune checkpoint inhibition. Here, we report therapeutic synergies of targeted cytotoxic aur...
Pharmaceutics, 2021
Recent advances in immunotherapy have revolutionized cancer therapy. Immunotherapies can engage t... more Recent advances in immunotherapy have revolutionized cancer therapy. Immunotherapies can engage the adaptive and innate arms of the immune system. Therapeutics targeting immune checkpoint inhibitors (i.e., CTLA-4; PD-1, and PD-L1) have shown efficacy for subsets of cancer patients by unleashing an adaptive antitumor immune response. Alternatively, small molecule immune modulators of the innate immune system such as toll-like receptor (TLR) agonists are being developed for cancer therapy. TLRs function as pattern recognition receptors to microbial products and are also involved in carcinogenesis. Reisquimod is a TLR 7/8 agonist that has antitumor efficacy. However, systemic delivery free resiquimod has proven to be challenging due to toxicity of nonspecific TLR 7/8 activation. Therefore, we developed a targeted peptide-drug conjugate strategy for systemic delivery of resiquimod. We designed an activatable cell penetrating peptide to deliver resiquimod specifically to the tumor tissue...