Genprex™ is a clinical stage gene therapy company developing a new approach to treating cancer, based on our novel proprietary technology platform, including our initial product candidate - Oncoprex™ immunogene therapy - or, Oncoprex. Our platform technologies are designed to administer cancer fighting genes by encapsulating them into nanoscale hollow spheres called nanovesicles, which are then administered intravenously and taken up by tumor cells where they express proteins that are missing or found in low quantities. Oncoprex has a multimodal mechanism of action whereby it interrupts cell signaling pathways that cause replication and proliferation of cancer cells, re-establishes pathways for apoptosis (or programmed cell death) in cancer cells, and modulates the immune response against cancer cells. Oncoprex has also been shown to block mechanisms that create drug resistance. We are currently conducting the second phase of a Phase I/II clinical trial at The University of Texas MD Anderson Cancer Center in Houston, Texas.
Cancers are complex diseases that can start in any site in the body when a tissue grows out of control and inhibits the body’s normal functioning. At the cell level, cancers often involve the dysregulation of multiple genes and cellular pathways, leading to the cell’s inability to maintain proper cellular functions. Re-establishing or blocking these pathways can be done through many therapeutic approaches, including gene therapy. More general information about cancer can be found at The American Cancer Society.
Genprex’s research and development projects are focused on potential new treatments for lung cancer. Lung cancer is one of the most prevalent and deadly cancers worldwide. However, survival for late stage lung cancer has not improved significantly in the past 25 years despite radical advances in drug development and novel therapeutic standards. Our objective at Genprex is to develop 21st century gene therapies to improve outcomes.
We hold a portfolio of 30 issued and 2 pending patents covering our technologies and targeted molecular therapies. Our research and development is focused around better understanding cancer immuno-biology so that we can identify patients who will respond well to certain drugs. This is the premise of personalized medicine, whereby certain cancer molecular profiles can be specific targets for drugs and biologics.
Targeted molecular cancer therapies offer new options for cancer patients.
Our lead product candidate, Oncoprex, consists of a TUSC2 gene encapsulated in a positively charged nanovesicle made from lipid molecules with a positive electrical charge. Oncoprex is injected intravenously and can specifically target cancer cells, which generally have a negative electrical charge. Once Oncoprex is taken up into a cancer cell, the TUSC2 gene is expressed into a protein that is capable of restoring certain defective functions arising in the cancer cell. Oncoprex has a multimodal mechanism of action whereby it interrupts cell signaling pathways that cause replication and proliferation of cancer cells, re-establishes pathways for programmed cell death, or apoptosis, in cancer cells, and modulates the immune response against cancer cells. Oncoprex has also been shown to block mechanisms that create drug resistance.
Oncoprex is a pan-kinase inhibitor shown to simultaneously inhibit the EGFR and AKT oncogenic kinase pathways in vitro and in vivo. Once the cancer cell takes up the nanovesicle containing TUSC2, it is reprogrammed to die. Resistance to targeted drugs and checkpoint inhibitors develop through activation of alternate bypass pathways. For example, when PD-1 is blocked, the TIM-3 checkpoint is up-regulated. We believe that Oncoprex’ multimodal activity will block emerging bypass pathways, reducing the probability that drug resistance develops.
Our cancer gene therapy platform and its innovative delivery system are highly targeted. While the TUSC2 gene induces apoptosis in cancer cells which have low or absent TUSC2 expression, TUSC2 delivered by nanovesicles to normal cells is well tolerated relative to other lung cancer drugs. Moreover, the nanovesicles are taken up by tumor cells after Oncoprex treatment at 10 to 25 times the rate at which they are taken up by tumor cells before Oncoprex treatment, because of selective endocytosis of the nanovesicle lipid formulation and the enhanced permeability and retention, or EPR, characteristics of tumor vasculature, without the need for external ligands, or binding molecules.
Our preclinical and clinical data indicate that Oncoprex may be effective alone or in combination with targeted small molecule therapies such as erlotinib and gefitinib, and immunotherapies, thereby facilitating the action of these other therapies, allowing use in expanded populations of patients.
Clinical and pre-clinical data have shown that when Oncoprex is combined with EGFR TKI therapy, such as erlotinib and gefitinib, in EGFR mutated resistant cancers, the combination therapy overcomes intrinsic and acquired therapeutic resistance by simultaneously inactivating the EGFR and the AKT signaling pathways to restore apoptotic pathways. Clinical and preclinical data also indicate that Oncoprex, when combined with EGFR TKIs, such as erlotinib and gefitinib, provides a synergistic effect that could also benefit the larger population of NSCLC patients who are EGFR negative (which means they are not expected to benefit from EGFR TKI drugs alone). Further, our data show that Oncoprex may re-sensitize EGFR positive patients who become resistant to, and therefore no longer benefit from, EGFR TKIs alone.
Many currently approved cancer therapeutics target only single molecules or a single specific genetic abnormality related to driving the proliferation and survival of cancer cells. In contrast, Oncoprex works by targeting several molecules within the cancer cell to target and kill cancer cells, to block mechanisms that create drug resistance, and to stimulate the natural immune response.
Moreover, Oncoprex works synergistically with other cancer drugs to produce more effective anti-cancer effects than either produces alone. Our clinical and preclinical data indicate that Oncoprex can work synergistically with:
In conjunction with these other drugs, Oncoprex can mediate an anti-tumor response through up-regulation of NK cells, CD8+ T cells, and down-regulation of regulatory T cells, or Tregs, and PD-L1 receptors, activate alternative immune mechanisms with the potential to complement checkpoint inhibitors. Published data indicate that effectiveness of these kinase inhibitors and immunotherapy drugs is enhanced when they are combined with Oncoprex.
The Genprex gene therapy platform consists of anti-cancer genes encapsulated in nanovesicles that are delivered intravenously. The Oncoprex TUSC2 gene is encapsulated in a positively charged nanovesicle that binds to actively replicating (and, therefore, negatively charged) cancer cells and then enters the cancer cell through selective endocytosis.
The particle size is small enough to allow Oncoprex to cross tight barriers in the lung but large enough to avoid accumulation or clearance in the liver, spleen and kidney. The cationic charge of the nanovesicle targets cancer cells, and direct nanovesicle fusion avoids target cell endocytosis. A Phase I clinical trial showed that intravenous Oncoprex therapy was proven to selectively and preferentially target primary and metastatic tumor cells, resulting in clinically significant anticancer activity. The nanovesicles are non-immunogenic, allowing repetitive therapeutic dosing and providing extended half-life in the circulation.
Our nanovesicle delivery platform is applicable to delivery of a range of therapeutic and prophylactic plasmid DNAs and RNA interference constructs. The nanovesicle manufacturing methods we and our collaborators have developed have been optimized and are useful for a wide array of disease treatments. Our nanovesicles are clinically proven to deliver molecular kinase inhibitors effectively. Clinical outcomes demonstrated that the delivery system used in Oncoprex is well tolerated in humans and can safely deliver high therapeutic doses.
We are developing Oncoprex, our lead product candidate, to be administered with erlotinib for NSCLC. We are also conducting preclinical research with the goal of developing Oncoprex to be administered with targeted therapies in other solid tumors, and with immunotherapies in NSCLC and other solid tumors. In addition, we have conducted and plan to continue research into other tumor suppressor genes associated with chromosome 3p21.3, as well as other potential applications of our immunogene therapy platform. Our current research and development pipeline is shown below.
A phase I dose escalation trial was conducted at The University of Texas MD Anderson Cancer Center (UTMDACC) evaluating intravenous Oncoprex (TUSC2/FUS1) monotherapy in stage IV recurrent, metastatic lung cancer patients. The study showed for the first time that a tumor suppressor gene can be delivered intravenously and selectively to a patient’s cancer cells using a systemic nanovesicle vector, express high levels of mRNA and protein in cancer cells in both primary and distant metastatic tumor sites, alter relevant pathways in the cancer cell, and mediate clinically beneficial anti-cancer activity. Oncoprex was well tolerated with tumor responses noted in lung primary and metastatic tumors. The publication is available here.
A phase I/II clinical trial has been designed and accepted by FDA to evaluate intravenous Oncoprex in combination with Tarceva® (erlotinib) in stage IIIB/IV lung cancer patients without an activating EGFR mutation and in patients with an activating EGFR mutation whose cancer has progressed on erlotinib therapy. Patients without the EGFR mutation represent the vast majority of lung cancer patients. However, such patients are generally not candidates for Tarceva therapy.
Phase I (2014-2016)
Enrollment in the Phase I portion of the combination trial commenced in 2014. The Phase I portion of the trial was a dose escalation study seeking primarily to establish the safety profile of the combination of TUSC2 and erlotinib and to establish a Maximum Tolerated Dose (MTD) to be delivered to patients in the Phase II portion of trial. Inclusion criteria of the ongoing Phase II trial consist of adult patients who had either failed or are not candidates for TKI and showed disease progression.
Phase II (2016-present)
The first subject enrolled in the Phase II portion in 2016. In the Phase II Combination Trial, subjects receive Oncoprex in combination with erlotinib every 21 days until the occurrence of progressive disease (PD), unacceptable toxicity, withdrawal of consent, or study treatment discontinuation for other reasons, whichever occurs first. We believe that the results from the ongoing Phase II trial to date are encouraging. At the time of analysis in Q2 2017, out of 10 patients, 9 had received 2 or more cycles and were therefore evaluable for response. Four patients had tumor regression. The median duration of response is 3 months. The disease control rate (CR+PR+SD > 8weeks) was 78%, which substantially exceeds the 7% response rate (with no CRs) and 58% disease control rate reported for the LUX-Lung 1 trial, a clinical trial of afatinib in a comparable group of patients.
One patient in the Phase II combination trial had a Complete Response, or CR, under the Response Evaluation Criteria in Solid Tumors, or RECIST. This patient, a 58 year old female, upon enrollment in the study had metastatic NSCLC status following 6 cycles of pemetrexed and carboplatin and 2 cycles of maintenance pemetrexed with cancer progression. The patient’s tumor has EGFR exon 18 and 20 missense mutations, which are not sensitive to erlotinib. This patient had disappearance of both the lung primary tumor and the lung, liver, and lymph node metastases.
More information about this trial can be found at ClinicalTrials.gov
Tarceva® is a registered trademark of Astellas and the Roche Group of companies.
TUSC2 (formerly known as FUS1, the active anti-cancer agent in OncoprexTM) in combination with PD-1 checkpoint inhibition has a significantly greater anti-tumor effect in lung cancer than either agent alone. The research also shows that TUSC2 in combination with PD-1 blockade has synergistic activity in upregulating natural killer (NK) cells, correlated with prolonged survival in mice.
TUSC2 is a tumor suppressor gene that is lacking in cancer cells of many different cancer types, including non-small cell lung cancer (NSCLC). It is a pan-kinase inhibitor that has been shown in-vivo to affect cell proliferation and programmed cell death. PD-1 is a protein found on certain types of T cells, which are part of the immune system. Because PD-1 prevents T cells from attacking other cells, including in some cases cancer cells, inhibiting PD-1 can facilitate the immune response to cancer.
The research was presented at the 2017 Annual Meeting of the American Association of Cancer Research in Washington, D.C.
Tumor suppressor gene TUSC2/FUS1 (TUSC2) is frequently inactivated early in lung cancer development. TUSC2 mediates apoptosis in cancer cells but not normal cells by upregulation of the intrinsic apoptotic pathway. No drug strategies currently exist targeting loss-of–function genetic abnormalities. We report the first in-human systemic gene therapy clinical trial of tumor suppressor gene TUSC2.
DNA alkylating agents such as platinum and nitrogen mustard are effective cancer chemotherapeutics. They kill proliferating tumor cells by inducing high levels of DNA damage leading to cell-cycle arrest and cell death. However, their highly toxic side effects and the common drug resistance exhibited in tumors limit their anticancer efficacy and clinical benefits. Here we describe a novel anticancer therapeutic strategy using a new class of rationally designed dual DNA alkylating/HDAC inhibitors combined with nanovesicle-mediated gene therapy targeting the DNA damage/repair pathway in human NSCLC and SCLC cells.
TUSC2, a novel tumor suppressor gene in the human chromosome 3p21.3 region, is deleted in many cancers. A phase I clinical trial assessing TUSC2-mediated molecular therapy has reported antitumor activity in lung cancer patients. Previous studies showed that TUSC2 regulates the activation of multiple oncogenic kinases. MK2206 is a highly selective non-ATP-competitive allosteric inhibitor of AKT currently being evaluated in early-phase clinical trials for treatment of patients with lung cancer.
A poster describing a phase I clinical trial investigating Oncoprex® (intravenous TUSC2 nanovesicles) used a single agent in recurrent, metastatic lung cancer patients. The dose escalation clinical trial was conducted at The University of Texas MD Anderson Cancer Center. The poster was presented at the 2011 Annual Meeting of the American Association for Cancer Research (AACR) and received a Highly Rated Paper award from AACR.
An abstract describing a phase I clinical trial investigating Oncoprex® (intravenous TUSC2 nanovesicles) used a single agent in recurrent, metastatic lung cancer patients. The dose escalation clinical trial was conducted at The University of Texas MD Anderson Cancer Center. The abstract was published in the Proceedings of the 2011 Annual Meeting of the American Association for Cancer Research (AACR) and was awarded a Highly Rated Paper by AACR.