LIXTE has developed a series of novel serine/threonine phosphatase inhibitors (s/t ptases). THE s/t ptases are ubiquitous enzymes that regulate many cell signaling networks important to cell growth, division and death. They have long been appreciated as potentially important targets for anti-cancer drugs. Because of the multifunctionality of these enzymes however, it has been widely held that pharmacologic inhibitors of s/t ptases would be too toxic to allow their development as anti-cancer treatments. Lixte has shown that this is not the case. The lead clinical compound, LB-100, was well tolerated at doses associated with objective regression (significant tumor shrinkage) and/or arrest of tumor progression in patients with progressive cancers who had failed treatment with standard and experimental regimens (Chung 2016). The development of anti-s/t ptases promises to be a major new advance in cancer therapy (Zhuang 2009).

Preclinical studies show that LB-100 itself inhibits a spectrum of human cancers and that LB-100 combined with standard cytotoxic drugs and/or radiation potentiates their effectiveness against hematologic and solid tumor cancers without enhancing toxicity. Recently, given at very low doses in animal models of cancer, LB-100 markedly increased the effectiveness of a PD-1 blocker (Ho 2017). This finding raises the possibility that LB-100 may further expand the value of the burgeoning field of cancer immunotherapy.

Although Lixte’s focus has been on developing anti-cancer drugs, several leading academic centers, studying LB-100 under material transfer agreements with Lixte, have generated preclinical data indicating that LB-100 may be therapeutically effective in important non-neoplastic diseases. This rather extraordinary situation stems from the fact that dysregulation of PP2A function is not only a feature of many cancers but also a significant component of the basic inflammatory response elicited by diverse types of injury, which include lipid buildup in blood vessels (type 2 diabetes, Bharath 2015), acute oxygen deprivation (myocardial infarction and stroke, MI/S) Weinbrenner 1998, Zhang 2008, Heijman 2013), and aversive physical and/or psychological trauma (major depressive disorder, MDD (Lecca 2016). Lixte has a substantial patent portfolio covering composition of matter for its PP2A inhibitors and their use in the therapy of a broad spectrum of human diseases.

LB-100 Mechanisms of Action

LB-100 delivers an active metabolite into the cell, potently inhibiting specifically the s/t ptases PP2A. Inhibition of PP2A markedly potentiates the effectiveness of standard anti-cancer drugs and X-ray that exert their clinical benefit by damaging DNA thereby inhibiting faithful cell division.

Although the growth of normal cells including those of the bone marrow, GI tract, and hair is also impaired by cytotoxic cancer treatment, cancer cells often have acquired genetic damage that permits their unrestrained growth but also reduces their ability to repair DNA damage. Inhibition of PP2A by LB-100 further impairs DNA repair to a greater extent in the cancer cell than in the normal cell providing more selective killing (Lu 2009, Zhuang 2009, Wei 2013, Hong 2015).

LB-100 used alone has modest inhibitory activity against many cancers in model systems, but certain human cancers, possessing unique genetic changes in addition to those reducing DNA damage repair, are particularly vulnerable to inhibition of PP2A by LB-100. Among these is myelodysplastic syndrome (MDS), an increasingly common neoplastic disease, especially in persons aged 65 and older, characterized by failure of the bone marrow. In particular, a variant of MDS termed del(5q)MDS is missing ~50% of its PP2A activity rendering this tumor potentially vulnerable to further pharmacologic inhibition of PP2A (Sallman 2015). There is presently only one drug approved for del(5q) MDS patients and none for MDS in general.

Other cancers, notably small cell lung cancer (SCLC) and liver cancer (hepatocellular cancer, HCC), have acquired genetic abnormalities, which render them sensitive to inhibition of PP2A by a process termed synthetic lethality (Bian 2015). Preclinical studies have shown that both SCLC (Lixte, unpublished) and HCC (Zhang 2008, Bai 2015) are sensitive to PP2A inhibition by LB-100 alone and especially so when LB-100 is combined with drugs used as standard treatment for these diseases. SCLC is the lung cancer variant associated with cigarette smoke and comprises about 15% of all lung cancers. HCC is the 5th most common cancer in the world and the 3rd leading cause of death from cancer with the majority of cases being in Asia. There is no satisfactory treatment available for either of these devastating tumors.

Scientists at the National Institute of Neurological Disorders and Stroke (NINDS), have conducted pre-clinical studies of LB-100 showing anti-cancer activity in models of human brain tumors including glioblastoma multiforme (GBM) (Lu 2009), medulloblastoma (Ho 2015), and malignant meningioma (Ho 2018). Studies of LB-100 and analogs in models of human brain tumors of adults and children are continuing under a Material-Cooperative Research and Development Agreement (M-CRADA) with the National Cancer Institute (NCI). NCI also has an FDA approved clinical pharmacokinetic (non-therapeutic) study of LB-100 (Phase 0 Trial, NCT03027388) in patients with recurrent GBM to assess penetration of the drug into these highly malignant tumors. The rationale for this study is that LB-100 and analogs potentiate the anti-tumor activity of both x-ray and the drug, temozolomide, which are the mainstays of treatment for GBM. If LB-100 penetrates GBMs, the addition of LB-100 to the standard regimen may improve its effectiveness.

Near Term Objectives—Clinical Cancer Trials

Lixte’s immediate goals are to demonstrate significant therapeutic benefit of LB-100 against one or more specific human cancers in Phase 2 trials. It is clear from multiple preclinical studies of LB-100 that Lixte has several attractive targets for new therapies incorporating LB-100. The next studies Lixte would like to pursue are:

1) A Phase 1b/2 clinical trial of LB-100 as a single agent in the treatment of patients with del(5q) myelodysplastic syndrome failing first line therapy.

2) a Phase 1b/2 randomized trial in previously untreated patients with small cell lung cancer (SCLC), comparing the standard regimen of carboplatin/etoposide to the same regimen plus LB-100.

3) a Phase 1b/2 randomized trial in previously treated patients with hepatocellular cancer, comparing doxorubicin alone to doxorubicin plus LB-100 or comparing LB-100 plus one of the new immune therapy drugs to the immune therapy drug alone.

Lixte had expected that LB-100 would be most effective against cancers deficient in PP2A as in del(5q)MDS and when combined with cytotoxic anti-cancer drugs and x-ray to interfere with repair of DNA-damage as in SCLC. However, early pre-clinical immunotherapy data showing that LB-100 potentiates the anti-cancer activity of PD-1 raises the possibility that LB-100 may also enhance the efficacy of so-called 'immune checkpoint blockers'—agents that allow the patients' own immune system to attack their own cancers.



PP2A mediates a number of different signaling pathways and is of fundamental importance to several otherwise seemingly unrelated disease entities. For example, PP2A is an essential component of the response of normal cells to deprivation of oxygen (ischemia). During ischemia, there are abnormal increases in the amounts of PP2A in tissues, particularly in blood vessels, which appear to contribute to the extent of tissue damage. In animal models, inhibition of PP2A even instituted after the induction of acute ischemia reduces the extent of tissue damage. Lixte seeks a partner to jointly explore the ability of LB-100 to decrease tissue damage in models of stroke, myocardial infarction (Weinbrenner 1998), and diabetic vascular disease (Bharath 2015).


There are few effective therapies for the treatment of resistant severe depression (major depressive disorder (MAD). It has recently been demonstrated in a widely used mouse model that the induction of depression is associated with neuronal hyperactivity and an increase in the activity of PP2A in the lateral habenula (LBh). The LBh is the site in the brain associated with depression in animals and humans and is the target of experimental therapies for MDD such as deep brain stimulation. In conditioned mice, parenteral administration of a LB-100 is associated with elimination of signs of depression and normalization of neuronal and PP2A activity in the LBh (Lecca 2016). LB-100 at doses comparable to doses effective in correcting signs of depression in the mouse model have been shown to be non-toxic in the phase I trials of LB-100. Lixte believes that if further preclinical studies confirm the observations of Lecca and colleagues, a proof of concept trial of LB-100 for the treatment of resistant severe depression would be a reasonable as there is an urgent need for better treatments for this challenging illness.


Deacetylase inhibitors (DACi) prevent the removal of a chemical group (acetyl group) modifier from proteins. DACi have been studied primarily as modifiers of gene expression. When a class of proteins, the histones, is acetylated (carry an acetyl group) the genetic material (DNA) is more accessible (active) than when the acetyl groups are removed by deacetylases. Because disordered gene regulation is one hallmark of cancer cells, histone deacetylase inhibitors (HDACi) have been studied intensely as anti-cancer drugs and several have been approved for treatment of a relatively rare lymphoma of the skin. Lixte has developed a novel group of HDACi which appear to be more stable and potentially possess broader actions than other HDACi and seeks a partner to develop these compounds for potential treatment of specific non-malignant diseases as described below.


Two Lixte HDACi, LB-201 and LB-205, inhibit the accelerated breakdown of "misfolded” proteins responsible for enzyme deficiencies in several hereditary diseases including Gaucher disease, neurofibromatosis 2 and von Hippel-Lindau disease. Exposure of cells with mutant proteins responsible for these diseases leads to stabilization of the proteins and potentially clinically significant increases in enzyme function. It appears that HDACi inhibit the machinery responsible for the rapid destruction of these functional but mutant enzymes. Given the relatively low toxicity of HDACi in general, and of Lixte's compounds in particular, the LB-200 series of drugs have potential for the therapy of several inherited diseases for which better treatments are sorely needed. In particular, if LB-201 or LB-205 stabilizes the mutant protein causing Gaucher disease, glucocerebrosidase, in vivo as it does in vitro, the compounds may reduce the amount of enzyme replacement therapy required for treatment of non-neurologic Gaucher disease. Because LB-201 penetrates the blood brain barrier, it may be particularly beneficial in the treatment of neurologic forms of Gaucher disease in which enzyme replacement is currently ineffective.


Lixte's HDACis have also been studied for the prevention and treatment of a variety of chronic and acute neurologic diseases. Because of the relatively low toxicity of HDACIs in general, Lixte's LB-201 was evaluated for its ability to reduce toxicity of various biochemical stresses in models of brain cell (neuron) injury. LB-201 was significantly protective against acute injury in these cell culture models, and a homolog, LB-205, reduced the extent of brain injury in rodent models of traumatic brain injury (TBI).


Because acetylation/deacetylation signaling pathways are essential components of the regulated growth of many types of organisms, Lixte's compounds were assessed for anti-fungal activity. Several compounds of the LB-200 series are active against a panel of clinical isolates of fungal pathogens. A topical formulation of LB-201 is curative for two of the most common dermal fungal infections of humans and animals in a guinea pig model, which is generally accepted as a reliable surrogate for human skin infections.


Bai X et al. (2014) Inhibition of protein phosphatase 2A enhances cytotoxicity and accessibility of chemotherapeutic drugs to hepatocellular carcinomas. Molecular Cancer Therapeutics (2014), 13(8), 2062-72.

Bharath L et al. (2015) Ceramide initiated protein phosphatase 2A activation contributes to arterial dysfunction in vivo. Diabetes (2015), 64(11), 3914-26.

Bian Y et al. (2014) Synthetic genetic array screen identifies PP2A as a therapeutic target in Mad2-overexpressing tumors. Proceedings of the National Academy of Sciences (PNAS) (2014), 111(4), 1628–1633.

Chung V et al (2016) Safety, Tolerability, and Preliminary Activity of LB-100, an Inhibitor of Protein Phosphatase 2A,in Patients with Relapsed Solid Tumors: An Open-Label, Dose Escalation, First-in-Human, Phase I Trial. Online First December 30, 2016; DOI: 10.1158/1078-0432.CCR-16-2299

Heijman J et al. (2013) Function and regulation of serine/threonine phosphatases in the healthy and diseased heart. Journal of Molecular and Cellular Cardiology (2013), 64, 90–98.

Ho et al. (2018) Pharmacologic inhibition of protein phosphatase-2A achieves durable immune-mediated antitumor activity when combined with PD-1 blockade. Nature Communications (2018) 9:2126.

Ho W et al. (2016) PP2A inhibition with LB100 enhances cisplatin cytotoxicity and overcomes cisplatin resistance in medulloblastoma cells. Oncotarget (2016), 7(11), 12447–12463.

Ho W et al. (2017). Protein phosphatase 2A inhibition, with a novel small molecule inhibitor, LB-100, achieves durable immune-mediated antitumor activity when combined with PD1 blockade in a preclinical model. Cancer Research 77(13 Supplement):LB-193· July 2017 Abstract.

Ho W et al. (2018) LB-100, a novel Protein Phosphatase 2A (PP2A) inhibitor, sensitizes malignant meningioma cells to the therapeutic effects of radiation. Cancer Letters (2018) 415, 217-226.

Hong C et al. (2015) LB100, a Small Molecule Inhibitor of PP2A with Potent Chemo- and Radio-sensitizing Potential. Cancer Biology & Therapy (2015), 16(6), 821-33.

Lecca S et al. (2016) Rescue of GABAB and GIRK function in the lateral habenula by protein phosphatase 2A inhibition ameliorates depression-like phenotypes in mice. Nature Medicine (2016), 22(3), 254-61.

Lu J et al. (2009) Inhibition of serine/threonine phosphatase PP2A enhances cancer chemotherapy by blocking DNA damage induced defense mechanisms. Proceedings of the National Academy of Sciences (PNAS) (2009), 106(28), 11697–11702.

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Wei D et al. (2013) Inhibition of Protein Phosphatase 2A Radiosensitizes Pancreatic Cancers by Modulating CDC25C/CDK1 and Homologous Recombination Repair. Clinical Cancer Research (2013), 19(16), 4422-4432. Weinbrenner C et al. (1998) Fostriecin, an Inhibitor of Protein Phosphatase 2A, Limits Myocardial Infarct Size Even When Administered After Onset of Ischemia. Circulation (1998), 98, 899-905.

Xiao et al. (2018) B-Cell-Specific Diversion of Glucose Carbon Utilization Reveals a Unique Vulnerability in B Cell Malignancies. Cell (2018) 173, 1-15.

Zhang S et al. (2008) Clinicopathologic significance of mitotic arrest defective protein 2 overexpression in hepatocellular carcinoma. Human Pathology (2008), 39, 1827–1834.

Zhuang Z et al. (2009) Enhancement of cancer chemotherapy by simultaneously altering cell cycle progression and DNA-damage defenses through global modification of the serine/threonine phospho-proteome. Cell Cycle (2009), 8(20), 3303-3306.

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