Document text
Principal Investigator: Donald Davidson
Organization: CREATIVE BIOTHERAPEUTICS, LLC
Fiscal Year: 2024
Award: $400,000
Funding agency: National Cancer Institute
PROJECT SUMMARY
Brain cancers are the leading cause of disease-related death in children and in adults under the age of 40
years old. Even with aggressive treatments that include maximal surgical resection, stereotactic radiosurgery,
whole-brain radiation therapy, chemotherapy, molecularly targeted therapeutics, and immunotherapies, the
recurrence rates for many brain cancers are nearly 100%. Despite the hundreds of clinical trials and combination
therapies tested, the mortality rates have only slightly decreased. According to the American Cancer Society, it
is estimated that there will be over 24,000 adults and children with primary brain cancer in the US in 2023 with
no available medications that can reverse drug resistant brain cancer recurrences. When secondary brain
metastases from other primary cancers like breast, melanoma and lung are included, it is estimated that there
will be over 300,000 patients with secondary brain metastases this year in the US. These patients are confronted
with a mixed blessing of longer initial treatment survival but an increased incidence of secondary, drug resistant
brain tumors. Much like primary brain cancer, when other cancers metastasize to the brain, they are almost
always lethal. New therapies that can target adult and pediatric drug resistant recurrent primary and secondary
brain cancers are badly needed.
Creative BioTherapeutics, has discovered that recurrent drug resistant cancers up-regulate a survival
pathway resulting in the expression and secretion of an extracellular Glucose-Regulated Protein 78 (ecGRP78)
in the tumor microenvironment. Our research shows that ecGRP78 is important for drug and immune resistance
as well as glioma stem cell formation. Cell surface bound ecGRP78 has been found on breast, lung, ovarian,
prostate, melanoma, multiple myeloma, colon, pediatric and adult brain tumors and not on normal cells. We have
found that ecGRP78 stabilizes essential oncofetal proteins, ROR1 and Cripto, along with the checkpoint protein,
PD-L1, on tumor and immune cell surfaces inducing a cascade of events to increase drug resistance, immune
suppression, and cancer stem cell formation. As such, we designed and developed several anti-cancer therapies
to specifically block the N-terminal domain of ecGRP78 from binding to and stabilizing these pro-tumorigenic
proteins on the tumor surface without disrupting normal cell function. We can now show that our lead inhibitor,
CBT300, in vitro can a) induce apoptosis of drug resistant tumor cells, b) eliminate drug and immune resistance
showing synergistic effects with chemotherapy and immunotherapy, c) decrease the amount of chemotherapy
needed, thus lowering the toxic side effects. Our in vivo results with human high grade glioma tumors in mice
treated with one of our ecGRP78 inhibitors displayed an increase in pathological complete responses of over
65% and an increase in median survival of 12 days or an estimated 2 years for human patients with no observable
toxicity. A non-toxic therapeutic alternative effective against recurrent brain tumors and brain metastasis
with increased overall survival and complete responses would prove to be paradigm altering.
Terms: <0-11 years old><15 year old><15 years of age><21+ years old><Abscission><Adult><Adult Human><Age><American Cancer Society><Anti-Cancer Agents><Antineoplastic Agents><Antineoplastic Drugs><Antineoplastics><Athymic Mice><Athymic Nude Mouse><B7-H1><B7H1><BiP gene><BiP protein><Binding><Biological Response Modifier Therapy><Biological Therapy><Brain><Brain Cancer><Brain Metastasis><Brain Neoplasia><Brain Neoplasms><Brain Nervous System><Brain Tumors><Breast><Breast Cancer><CD274><CFC1><CFC1 gene><CRC1 Gene><Cancer Drug><Cancer Treatment><Cancers><Cell Function><Cell Physiology><Cell Process><Cell surface><Cellular Function><Cellular Physiology><Cellular Process><Cessation of life><Chicago><Child><Child Youth><Childhood><Children (0-21)><Children's Hospital><Clinical Research><Clinical Study><Clinical Trials><Colon><Combined Modality Therapy><Cranial Irradiation><Creativeness><Criptic Protein Gene><Cripto><Cryptic Protein Gene><Death><Death Rate><Disease><Disorder><Documentation><Dose><Drug Industry><Drug resistance><Drugs><Encephalon><Essential Drugs><Event><Excision><External Domain><Extirpation><Extracellular Domain><Foundations><GRP78><GRP78 gene><Glial Cell Tumors><Glial Neoplasm><Glial Tumor><Glioblastoma><Glioma><Glucose-Regulated Protein, 78-kD><Goals><Grade IV Astrocytic Neoplasm><Grade IV Astrocytic Tumor><Grade IV Astrocytoma><HSPA5><HTX2><Heat-Shock 70-kD Protein 5><Human><Immune><Immune mediated therapy><Immunes><Immunologically Directed Therapy><Immunosuppression><Immunosuppression Effect><Immunosuppressive Effect><Immunotherapy><In Vitro><In complete remission><In vivo analysis><Incidence><Induction of Apoptosis><Lead><Legal patent><Letters><Lung><Lung Respiratory System><Malignant Breast Neoplasm><Malignant Melanoma><Malignant Neoplasm Therapy><Malignant Neoplasm Treatment><Malignant Neoplasms><Malignant Tumor><Malignant Tumor of the Brain><Malignant neoplasm of brain><Medication><Melanoma><Metastasis><Metastasize><Metastatic Lesion><Metastatic Mass><Metastatic Neoplasm><Metastatic Neoplasm to the Brain><Metastatic Tumor><Metastatic Tumor to the Brain><Metastatic malignant neoplasm to brain><Mice><Mice Mammals><Modeling><Modern Man><Molecular Interaction><Mothers><Multimodal Therapy><Multimodal Treatment><Multiple Myeloma><Murine><Mus><N-terminal><NH2-terminal><NIH><NTRKR1><National Institutes of Health><Neoplasm Metastasis><Neoplastic Disease Chemotherapeutic Agents><Neuroglial Neoplasm><Neuroglial Tumor><Neurosphere><Neurosurgeon><Neurotrophic Tyrosine Kinase Receptor-Related 1><Normal Cell><Nude Mice><Oncologist><Operative Procedures><Operative Surgical Procedures><Ovarian><PD-L1><PDL-1><PDL1><Pain><Painful><Parents><Patents><Pathologic><Pathway interactions><Patients><Pb element><Pediatric Hospitals><Pharmaceutic Industry><Pharmaceutical Industry><Pharmaceutical Preparations><Phase><Plasma-Cell Myeloma><Primary Brain Neoplasms><Primary Brain Tumors><Progenitor Cells><Programmed Cell Death 1 Ligand 1><Programmed Death Ligand 1><Prostate><Prostate Gland><Prostatic Gland><Proteins><Protocol><Protocols documentation><Provider><ROR1><ROR1 gene><Radiation Surgery><Radiation therapy><Radiosurgery><Radiotherapeutics><Radiotherapy><Receptor Tyrosine Kinase-Like Orphan Receptor 1><Recurrence><Recurrent><Recurrent Malignant Neoplasm><Recurrent Malignant Tumor><Removal><Research><SBIR><Secondary Neoplasm><Secondary Tumor><Small Business Innovation Research><Small Business Innovation Research Grant><Son><Stable Disease><Stereotactic External Beam Irradiation><Stereotactic Radiosurgery><Stereotaxic Radiosurgery><Sterotactic External Beam Radiation><Subcellular Process><Surface><Surgical><Surgical Interventions><Surgical Procedure><Surgical Removal><Testing><Therapeutic><Toxic effect><Toxicities><Tumor Cell><Tumor-Specific Treatment Agents><United States National Institutes of Health><Work><adulthood><age 15 years><ages><aggressive therapy><aggressive treatment><anti-cancer><anti-cancer drug><anti-cancer therapy><biological therapeutic><biological treatment><biologically based therapeutics><biotherapeutics><biotherapy><blood-brain tumor barrier><blood-tumor barrier><bloodbrain tumor barrier><brain irradiation><brain micrometastasis><brain radiation><cancer metastasis><cancer microenvironment><cancer progenitor><cancer progenitor cells><cancer recurrence><cancer stem cell><cancer therapy><cancer-directed therapy><chemotherapy><combination therapy><combined modality treatment><combined treatment><complete response><cranial radiation><creativity><design><designing><determine efficacy><drug candidate><drug development><drug discovery><drug resistant><drug/agent><effective therapy><effective treatment><efficacy analysis><efficacy assessment><efficacy determination><efficacy evaluation><efficacy examination><evaluate efficacy><examine efficacy><experience><experiment><experimental research><experimental study><experiments><extracellular><family support><fifteen year old><fifteen years of age><fighting><glial-derived tumor><glioblastoma multiforme><glucose-regulated proteins><heavy metal Pb><heavy metal lead><humanized mice><humanized mouse><immune resistance><immune suppression><immune suppressive activity><immune suppressive function><immune therapeutic approach><immune therapeutic interventions><immune therapeutic regimens><immune therapeutic strategy><immune therapy><immune-based therapies><immune-based treatments><immune-resistant><immuno therapy><immunoglobulin heavy chain-binding protein><immunoresistance><immunosuppressive activity><immunosuppressive function><immunosuppressive response><in vivo><in vivo evaluation><in vivo testing><inhibitor><kids><lead candidate><malignancy><malignant breast tumor><malignant progenitor><malignant stem cell><molecular targeted therapeutics><molecular targeted therapies><molecular targeted treatment><mortality rate><mortality ratio><mouse model><multi-modal therapy><multi-modal treatment><murine model><myeloma><myelomatosis><neoplasm/cancer><neoplastic cell><neuro-surgeon><neuroglia neoplasm><neuroglia tumor><new drug treatments><new drugs><new pharmacological therapeutic><new therapeutics><new therapy><next generation therapeutics><novel><novel drug treatments><novel drugs><novel pharmaco-therapeutic><novel pharmacological therapeutic><novel therapeutics><novel therapy><oncofetal antigen><oncofetal proteins><parent><pathway><pediatric><programmed cell death ligand 1><programmed cell death protein ligand 1><protein death-ligand 1><pulmonary><radiation treatment><radio-surgery><refractory cancer><resection><resistance to Drug><resistant cancer><resistant to Drug><side effect><spongioblastoma multiforme><stem cells><surgery><treatment with radiation><tumor><tumor cell metastasis><tumor growth><tumor microenvironment><tumorigenic><tumors in the brain><youngster>