Next Generation Anthracycline

Our Goal: Reinventing a Cornerstone of Cancer Treatment with the Intent to Provide Safer and More Effective Chemotherapy

Chemotherapy continues to be a cornerstone of cancer therapy.  Despite the progress made with immunotherapy and precision medicine, the first-line treatment for many cancers continues to include chemotherapy.  Cumulative research data now allow for a better understanding of the mechanisms of anticancer activity as well as toxic side effects, providing the opportunity to design and develop improved chemotherapeutic agents that may be safer and more effective.  Annamycin is an anthracycline designed with this purpose in mind.  Anthracyclines are a class of chemotherapy drugs considered to be among the most effective available, and with a broader spectrum of anticancer activity than most other classes of chemotherapeutic agents. They are recognized for their pleiotropic (producing or having multiple effects) mechanisms of action and for DNA being their primary target.  In particular, anthracyclines interfere with an enzyme called “topoisomerase II,” resulting in damage to the DNA of rapidly replicating tumor cells.  Such DNA damage leads to tumor cell death in a process called “apoptosis” (programmed cell death).

Acute leukemia (including both AML and ALL) is among a number of cancer types that usually are treated with anthracyclines.  In the case of acute leukemia, anthracyclines are typically used in “induction therapy,” where the goal is to induce sufficient remission of patients’ tumor cells to allow for a curative bone marrow transplant.

Two key factors limit the safety and effectiveness of currently approved anthracyclines:  cardiotoxicity (potential to damage the heart) and multidrug resistance.  Annamycin shows promise to possibly overcome these two factors; if preliminary data are borne out, Annamycin may ultimately provide clinically meaningful benefits over currently approved anthracyclines in treating certain cancers.  Preliminary data from very early-stage clinical trials suggest acute leukemia as a potentially opportune indication in which to further study Annamycin.

For more information on this potential indication, click here.

One of the key dose-limiting toxicities associated with currently available anthracyclines (including the anthracycline in the recently approved drug, Vyxeos) is the propensity to induce life-threatening heart damage.  This is a particularly significant risk for pediatric leukemia patients, whose life spans can be severely shortened by the induction therapy intended to cure them of acute leukemia.  In the animal model recommended by the FDA as an indicator of human cardiotoxicity, the non-liposomal (free) form of Annamycin has been shown to be significantly less likely than doxorubicin to create heart lesions in mice, and the liposomal formulation (L-Annamycin) has been shown in these same models to have reduced cardiotoxicity to the point where it is unlikely to cause harm to human patients.  If this characteristic is shown to be the same in humans, it may allow L-Annamycin to be used more aggressively to help patients achieve remission.  This would be especially valuable in the case of pediatric acute leukemia (both AML and ALL) because of the potential impact of cardiotoxicity on long-term survival.  In our current Phase I/II trial for Annamycin, we are collecting data to further validate the design intent of Annamycin to have little or no cardiotoxicity.  Unless otherwise noted, all of our references to Annamycin refer to the liposomal form (L-Annamycin).

To learn more about cardiotoxicity, click here.

In addition, the effectiveness of currently approved anthracyclines is limited by their propensity for succumbing to “multidrug resistance.”  This can occur where, as a natural defense mechanism, transmembrane proteins acting as transporters (one type of which is referred to as a “P-glycoprotein pump” or “ABCB1 transporter”) develop on the outer surface of cells to expel drugs like anthracyclines.  In many instances, the likelihood of cardiotoxicity (and other serious side effects) prevents increasing the dosing of current therapies in order to overcome multidrug resistance.  As a result, most patients cannot receive current anthracyclines in doses that are adequate to produce lasting remission and thereby qualify for a bone marrow transplant.  A laboratory study has suggested that Annamycin may resist being expelled by P-glycoprotein pumps and similar multidrug resistance transporters, which may mean the drug circumvents multidrug resistance.  This characteristic has been shown in pre-clinical testing to allow for higher drug uptake in diseased cells, which we believe could allow for more effective induction therapy with less risk to the patient.

To learn more about multidrug resistance, click here.

Immune/Transcription Modulators

Enabling Immune Response and Inhibiting p-STAT3 and other Oncogenic Transcription Factors

We believe our WP1066 Portfolio (including lead drugs WP1066, WP1220 and WP1732) represents a novel class of agents capable of affecting, in a concerted way, key oncogenic targets, including the activated form of transcription factor, STAT3. A substantial body of published research has identified STAT3 as a master regulator of a wide range of tumors and has linked the activated form, p-STAT3, with the survival and progression of these tumors. For this reason, it is widely believed that inhibition of p-STAT3 may be an effective way to reduce or eliminate the progression of these diseases.

For a deeper understanding of cell signaling, STAT3 and the role of oncogenic transcription factors, click here.

The high level of anticancer activity demonstrated in multiple tumors in animal models by WP1066 and WP1732 is potentially related to their ability to also inhibit such important key oncogenic transcription factors like c-Myc and HIF-1α. And, in animal models testing a range of human tumor types, in addition to direct anticancer effects not related to the function of the immune system, our lead drug WP1066 has also been shown to boost immune response, in part by inhibiting activity of Regulatory T cells (Tregs), which are coopted by tumors to evade the immune system. We believe the dual effect of (1) directly inhibiting tumor growth and inducing tumor cell death and (2) separately boosting and directing the natural immune response to tumors is therapeutically highly promising. If additional, clinical data validate the two avenues of apparent activity, this class of drugs may be well-suited to treat a wide range of tumors, both as single agents and as critical elements of successful combination therapies with the intent of targeting some of the most difficult-to-treat cancers.

The recent oncology drug landscape has been dominated by immunotherapy, specifically by the development of checkpoint inhibitors.  In just the last 5 years, checkpoint inhibitors (such as Opdivo and Keytruda) have reached over $10 billion in annual revenues.  To put checkpoint inhibitor therapy into simple terms, the T-cells within our own immune systems should be capable of identifying tumor cells and destroying them before they destroy us.  Unfortunately, tumors develop the ability to prevent this natural immune response by regulating the expression of certain receptors referred to as “immune checkpoints” that then bind to T-cells and prevent them from attacking the tumor.  Immune checkpoint inhibitors are antibodies that block these receptor mechanisms and allow the T-cells to attack the tumor.

In certain types of tumors, like melanoma, checkpoint inhibitors work well and the results can be impressive, creating durable suppression of tumors where no other therapy had succeeded.  However, despite the outstanding results in select patients, checkpoint inhibitors benefit only a limited number of patients in certain cancers, and they are essentially not effective in what are called “non-responsive” tumors like glioblastoma and pancreatic cancer, among others.  As a result, companies are now focusing heavily on combination therapies, combining immune checkpoint inhibitors with chemotherapy, as well as other agents.  There appears to be tremendous demand and we believe there is a clear need for new chemotherapeutic agents that, by their specific mechanism of action, would produce potent combination effects with immune checkpoint inhibitors, and that additionally can boost immune system response on their own.  In this regard, there is early nonclinical evidence that WP1066, as a single agent, has the ability to reverse immune tolerance in brain tumor patients (Cancer Res, 67(20), 9630, 2007), and preliminary data in animal models that suggests WP1066 may have a potential for combination use with checkpoint inhibitors.

Recently published research papers have presented several findings that may point to major new opportunities for Moleculin’s WP1066 class of drugs.  One such article suggested that our STAT3 inhibitor WP1066 abrogated PD-L1/2 expression in cancer cells, and may be a useful agent in addition to checkpoint inhibitor immunotherapy in cancer patients (J Clin Exp Hematop, 57(1), 21-25, 2017).  Other published results show that CTLA4-induced immune suppression occurs primarily via an intrinsic STAT3 pathway, suggesting that, through its inhibition of activated STAT3, WP1066 might work well in combination with this checkpoint inhibitor (Cancer Res, 77(18), 5118–28, 2017).

A separate paper presents selected key transcription factors as being responsible for the upregulation of an often-targeted checkpoint actor in tumors known as PD-L1.  Some of the most important transcription factors identified were HIF-1α, c-Myc and STAT3, the very targets for which WP1066 was designed (Front Pharmacol, 2018 May 22, 9:536, doi: 10.3389/fphar.2018.00536, eCollection 2018).  In summary, although much of the data is nonclinical and all of it is fairly preliminary, we are optimistic that administration of WP1066 could lead to improved treatment results in many patients receiving checkpoint inhibitor therapy.

Metabolism/Glycosylation Inhibitors

Targeting Cancer’s Sweet Tooth

Science has recognized that many types of cancer cells have a unique metabolism, distinct from that of normal cells. Cancer cells’ dependence on glycolysis (a specific way of converting glucose into energy) to proliferate and metastasize has been described as the “Sweet tooth of cancer” and is a classic example of how the metabolisms of cancer cells and normal cells differ. Glycolysis is a glucose-intensive means of producing energy that is used by normal cells only if oxygen levels are low. However, many types of tumor cells are essentially addicted to glycolysis even in the presence of abundant oxygen. This is known as the “Warburg Effect” after its discoverer, Dr. Otto Warburg, and such tumors are said to be highly “glycolytic.”

This phenomenon of tumors relying preferentially on glycolysis and the resulting dramatic increase of glucose uptake to fulfill their metabolic demands has already been utilized very effectively in cancer diagnostics. It is the Warburg Effect that enables imaging of actively growing tumors by positron emission tomography (“PET scans”). This diagnostic test uses a fluorine-18 radiolabeled glucose decoy called F18DG that accumulates disproportionately in tumors, using the same process that increases glucose uptake and retention in cancer cells.

The success of PET scanning points to the potential therapeutic benefit of the tumor-specific inhibition of glycolysis that would block energy (adenosine triphosphate (“ATP”)) production and could potentially “starve tumor cells to death” and/or make them sensitive to other existing therapies, including radiotherapy. Unsuccessful attempts to realize this therapeutic potential have been made in the past, using a glucose decoy known as “2-deoxy-D-glucose” (2-DG). Those attempts to target the metabolism of tumor cells have failed, we believe, because of 2-DG’s lack of drug-like properties that include rapid metabolism, short half-life and limited tissue-organ distribution. Essentially, not enough 2-DG could be delivered to its intended target.

We have designed and are studying a novel and patented prodrug of 2-DG (WP1122). We believe WP1122 has the potential for developing into a technology platform for enabling increased cellular uptake, increased drug half-life and, importantly, enabling greater uptake and retention in organs where the most resistant and glycolytic tumors are localized, including the brain and pancreas.

For more on what allows WP1122 to provide drug-like properties to 2-DG, click here.

Altering Glycosylation to Enhance Immune Checkpoint Therapy

A recently published study (Am J Cancer Res, 8(9), 1837-1846, 2018) focused on the analysis of tumor resistance to immune checkpoint therapy.  The study found that a process known as glycosylation plays an important role in the ability of checkpoint receptors to suppress immune activity and thereby protect tumors from attack.  The researchers discovered that an alteration of the glycosylation of these receptor mechanisms could effectively prevent this evasion of the immune system.  And, importantly, this study found that 2-deoxyglucose, or 2-DG, was capable of making this alteration.  Although the data are preliminary, the findings suggest that 2-DG could act as an effective anticancer agent in combination with checkpoint inhibitors and potentially with other anticancer therapies.

Attempting to use 2-DG as a drug, however, faces the same problems discussed above.   2-DG’s short circulation time and lack of other drug-like properties mean the drug doesn’t stay in the system long enough or concentrate sufficiently in targeted organs, which severely limits its effectiveness.  This suggests a possible role for our patented drug candidate, WP1122.  Our product which is a prodrug of 2-DG, meaning it’s a molecule that can be converted into pharmacologically active 2-DG within the body of the patient.  The design of WP1122 allows for a longer circulation time and improved organ distribution, which should provide it a greater opportunity to become an effective drug.  We intend to study WP1122 for its ability to improve the performance of checkpoint inhibitors by reducing the effect of glycosylation.