A14: lead anti-cancer drug candidate

 

A14 is a small-molecule anti-cancer drug compound that is based on the naturally-occurring plant hormone methyl jasmonate. Methyl jasmonate has been the subject of keen interest by cancer scientists because of its low toxicity and its broad anti-cancer activity which appears to be based on two or more Mechanisms of Action (mitochondrial inhibitor, anti-angiogenic). Despite its great promise as a cancer drug, however, clinical development of the parent compound was hindered because it degraded so quickly when given systemically.

 

Our innovation begins by selecting an analog of methyl jasmonate, then improving its bioavailability using proprietary nano-engineering protocols.

 

A14 has been shown to have broad activity against both blood cancers (in cell lines) and several solid tumors (in cell lines and in mouse models). Our data show that we preserved the underlying anti-cancer mechanism(s) of the parent compound, but significantly improved bioavailability.

 

Importantly, recent data show that A14 also preserves the low toxicity of the parent compound.  When the parent compound was studied in a mouse T lymphoma EL-4 model, no toxicity was observed (236 mg/kg body weight; no toxicity at 2x dose - 47.2 mg/kg2 ) (Fingrut and Flescher 2002). When A14 was tested in mouse, using histopathological analysis, standard hematology and clinical chemistry analytical methods, there were no signs of toxicity in brain, liver, spleen, kidney, gastrointestinal and/or bone marrow (unpublished Nanocare data).

 

 

Acute Myeloid Leukemia

 

In 2014, an estimated 18,860 individuals in the US will be diagnosed with a kind of blood cancer called acute myeloid leukemia (AML).

 

Acute myeloid leukemia disproportionately affects older individuals (60% of whom are over age 65). Outcomes differ according to age and the genetic subtype of AML, but the average survival rate for all patients is only five years.

 

At the moment, the Standard-of-Care is two generic chemotherapeutic agents. Almost 75% of patients become drug-resistant within one year. Bone marrow (stem cell) transplants can be effective, but only if enough cancerous cells can be beaten back to allow the transplant to “take.” The current drug regimen is so difficult, that some patients choose to simply forego treatment.

 

There are a handful of drugs in the pipeline with promising new drugs therapies to treat AML, but there have been no significant therapeutic advances in the treatment of this form of blood cancer for almost 40 years.

 

 

A14’s promise for acute myeloid leukemia

 

When tested in cell lines that represent key blood cancers, A14 showed significant anti-cancer activity against AML and against another rare blood cancer, human acute lymphoblastic leukemia (ALL):

 

‒ Nomo-1, relevant to human acute myeloid leukemia (AML)

‒ MOLM-14, relevant to human acute myeloid leukemia (AML)

‒ CRL-2314 (TIB-152), relevant to human acute lymphoblastic leukemia (ALL)

 

Both because A14 has such low toxicity, and because it acts on cells differently than other types of drugs currently in development, our vision is that A14 can be administered safely to older patients, possibly in combination with other existing and perhaps new drug therapies.

 

 

Other A14 data: broad activity in vitro

 

A14 has been shown to inhibit a range of cancer cells, including cancer drug-resistant cells, in a dose-dependent manner.  This suggests that in principle A14 could be developed not only for blood cancers, but also for melanoma; breast cancer including drug-resistant breast cancer; kidney cancer; lung cancer; prostate cancer; ovarian cancer; and colon cancer.

 

A14 Variants Exhibit Cytotoxicity Against Range of Cancer Cell Types

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Other A14 data: selected activity in vivo (human colon cancer model)

 

A14 has been shown rapid onset of anti-cancer action in several models of human cancer, including breast cancer the human colon cancer model illustrated below.

 

Systemic A14 shrinks human colon tumor in human colon cancer mouse model
and disrupts tumor blood supply

 

AFTER 4 DAYS OF TREATMENT WITH A14:

 

 

A14-treated tumors (right) are more pale, suggesting reduced angiogenesis (blood vessel formation).

 

 

 

A14-treated tumors (right) have 284% (P<0.01) larger hemorrhagic tumor necrosis (N). Result suggests vascular disruption eg possibly anti-angiogenic Mechanism of Action (MOA).

 

 

 

A14-treated tumors (right lower panel) have impaired blood vessel formation and “leaky” red blood cells. Suggests that A14 has rapid onset of action disrupting formation of tumor blood supply.

 

 

 

 

 

 

 

Pipeline

 

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