Acute Myeloid Leukemia (AML) and Hodgkin’s Lymphoma (HL) are serious blood disorders that disrupt normal cell function and can progress rapidly without treatment. AML affects the bone marrow, impairing blood cell production, while HL is a cancer of the lymphatic system that weakens the body’s ability to fight infections. Despite advancements in treatment, there remains a critical need for more effective and targeted therapies. At PhorMed, we are pioneering new approaches to address these challenges and improve outcomes for patients facing these life-threatening diseases.
AML is an aggressive hematologic disorder ultimately leading to fatalities in approximately 80% of the patients. Other than the physiological symptoms, patients with AML have shown impediments of differentiation and proliferation of blood stem cells leading to apoptosis, i.e. undesired cell death. Numerous published studies have indicated that the impediments include critical protein syntheses for differentiation and proliferation. Therefore, it can be concluded that the cause of AML is at the genetic level, the abnormal or lack of normal expression at the DNA and/or RNA level in the cellular processes. Phorbol esters, including our proprietary RP-323 induce a broad spectrum of cellular effects including differentiation and proliferation (cell division) of hematopoietic cell lines.
Base on the above scientific evidence, PhorMed Inc. initiated and completed a Phase I clinical trial in the US using our proprietary phorbol ester, RP-323, with patients diagnosed with hematological malignancies. Together with a positive indication of the efficacy of RP-323 in differentiation and proliferation, the safety profile of treatment with RP-323 showed only transient short term side effects.
RP-323 is therefore a candidate for the treatment of acute myeloid leukemia.
How it Works in AML
The activity of RP-323 as a differentiating agent has been established by studies of HL-60 human promyelocytic cells and primary human leukemia cells obtained from patients. RP-323 induces a broad spectrum of biological effects that provide a basis for its usefulness in treating AML. At the cellular level, many of these effects may be mediated by protein kinase C. Protein kinase C is a family of phospholipid and calcium-dependent isozymes that are activated by diacylglycerol. RP-323 is able to activate protein kinase C in the absence of diacylglycerol. The targets of phosphorylation result in the activation of several processes involved in cellular differentiation, clearing the pathway along the full GM-CFS pathways from stem cell to white blood cell (see figure 1); proliferation and cytokine induction, working at multiple points to clear pathways and boost immune responses (see figure 2); mitogenesis; neurotransmission; hormone secretion; and/or can result in apoptosis, the death of cells (see figure 3). Two well-characterized transcription activation/repression pathways regulated by NF-kB and AP-1 transcription complexes appear to be regulated by protein kinase C.
A New Hope for AML Treatment
RP-323 demonstrates a broad range of biological effects, making it a promising candidate for AML treatment. By targeting both cellular and molecular mechanisms, RP-323 leverages the activation of Protein Kinase C (PKC) to combat the disease by:
- Differentiation: RP-323 facilitates the maturation of immature blood cells into functional white blood cells. This is crucial in AML, where immature blood cells proliferate uncontrollably.
- Stem Cell Signalling: RP-323 has the ability to directly inhibit the signalling pathways in AML stem cells, which are often resistant to standard treatments.
- Apoptosis: RP-323 can aid in signalling cancer cells to self-destruct. It activates an enzyme called Protein Kinase C (PKC), increasing the levels of specific molecules, such as ceramide and Nur77.
- Cytokine Induction: RP-323 stimulates the production of cytokines, small proteins that boost the immune system’s response against cancer cells.
Through its multi-faceted approach, RP-323 not only tackles cancer at its core but also provides a pathway for overcoming resistance to traditional therapies. Its unique mechanisms offer new opportunities for improving patient outcomes in AML.
RP-323 is a phorbol ester that induction proliferation and differentiation and/or apoptosis in multiple cell lines. RP-323 has been demonstrated to modulate the growth, differentiation, survival, function and metabolism of other primary cells and cell lines. The broad range of these phorbol-mediated biological effects suggests a role for this drug in the modulation of a variety of cellular processes including those that affect the development, progression and therapy of human malignancies. It has been shown to activate protein kinase C (PKC) and modulate the activity of multiple downstream signaling pathways including mitogen activated protein kinase (MAPK) pathways. By inducing PKC it causes the formation of NF Kappa leading to the formation of NF Kappa B which has the ability to regulate cellular responses by entering the nucleus of the cell. NF-Kappa B binds to the DNA, thereby inducing differentiation and proliferation, clearing the pathway along IL-7 and IL3 and possibly other pathways from stem cell (see figure 1); and cytokine induction, working at multiple points to clear pathways and boost immune responses (see figure 2), and/or apoptosis, the death of cells (see figure 3).
Innovative therapy for Treating Hodgkin’s Lymphoma
RP-323 has demonstrated a remarkable ability to influence a broad spectrum of cellular activities, positioning it as a promising candidate for the treatment of Hodgkin’s Lymphoma. By activating Protein Kinase C (PKC), RP-323 engages critical pathways that regulate cell growth, differentiation, survival, function, and metabolism, making it a vital tool in addressing human malignancies.
- Differentiation: By activating PKC, RP-323 can help immature blood cells develop into more specialized, functional types, stimulating the activation of NF-Kappa B which leads to the expression of NF-Kappa B regulated genes. This gene expression can promote the repairment and restoration of damaged cells.
- Apoptosis: Activation of Protein Kinase C by RP-323 can lead to increased levels of ceramide and upregulated Nur77, both of which can aid in signalling cancer cells to self-destruct, thereby reducing the size of tumors.
- Cytokine Induction: RP-323 stimulates the production of cytokines, small proteins that boost the immune system’s response against cancer cells.