Methods for determining drug efficacy for the treatment of diffuse large b-cell lymphoma, multiple myeloma, and myeloid cancers

Abstract

Provided herein, in some embodiments, are methods of using certain cereblon-associated proteins, such as Aiolos, Ikaros, interferon (IFN), and IFN pathway proteins, casein kinase 1, alpha 1 (CSNK1A1), and ZFP9, as biomarkers for use in predicting and monitoring clinical sensitivity and therapeutic response to certain compounds in patients having various diseases and disorders, such as cancers (e.g., diffuse large B-cell lymphoma (DLBCL), multiple myeloma (MM), myelodysplasia syndromes (MDS) and acute myeloid leukemia (AML)) and IFN-associated disorders. Also provided herein, in certain embodiments, are methods of determining the efficacy of an immunomodulatory compound.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS[0001]This application claims the benefit of priority to U.S. Provisional Application No. 61 / 913,003 filed Dec. 6, 2013, U.S. Provisional Application No. 61 / 947,963 filed Mar. 4, 2014, U.S. Provisional Application No. 61 / 990,621 filed May 8, 2014, U.S. Provisional Application No. 62 / 061,050 filed Oct. 7, 2014, U.S. Provisional Application No. 62 / 064,413 filed Oct. 15, 2014, U.S. Provisional Application No. 62 / 077,835 filed Nov. 10, 2014, and U.S. Provisional Application No. 62 / 087,111 filed Dec. 3, 2014, each of which is incorporated herein by reference in its entirety.1 FIELD[0002]Provided herein, in some embodiments, are methods of using certain cereblon-associated proteins, such as Aiolos, Ikaros, interferon (IFN), and IFN pathway proteins, casein kinase 1, alpha 1 (CSNK1A1 or CK1α), and ZFP91 as biomarkers for use in predicting and monitoring clinical sensitivity and therapeutic response to certain compounds in patients having various disea...

AI Technical Summary

Problems solved by technology

However, options for the treatment of cancer are limited.

For example, in the case of blood cancers (e.g., multiple myeloma), few treatment options are available, especially when conventional chemotherapy fails and bone-marrow transplantation is not an option.

Although viruses reportedly cause several forms of leukemia in animals, causes of leukemia in humans are to a large extent unknown.

However, uncontrolled growth of these cells leads to bone pain and fractures, anemia, infections, and other complications.

MDS is characterized by a cellular marrow with impaired morphology and maturation (dysmyelopoiesis), peripheral blood cytopenias, and a variable risk of progression to acute leukemia, resulting from ineffective blood cell production.

The approach for patients with relapsed or refractory disease relies heavily on experimental treatments followed by stem cell transplantation, which may not be appropriate for patients with a poor performance status or advanced age.

Thus, inhibition of HIF1 may slow or reverse tumor cell metabolism.

All of these approaches may pose significant drawbacks for the patient.

Surgery, for example, may be contraindicated due to the health of a patient or may be unacceptable to the patient.

Additionally, surgery may not completely remove neoplastic tissue.

Radiation therapy is only effective when the neoplastic tissue exhibits a higher sensitivity to radiation than normal tissue.

Radiation therapy can also often elicit serious side effects.

Certain biological and other therapies are limited in number and may produce side effects such as rashes or swellings, flu-like symptoms, including fever, chills and fatigue, digestive tract problems or allergic reactions.

Despite availability of a variety of chemotherapeutic agents, chemotherapy has many drawbacks.

Almost all chemotherapeutic agents are toxic, and chemotherapy causes significant and often dangerous side effects including severe nausea, bone marrow depression, and immunosuppression.

Because of the drug resistance, many cancers prove refractory to standard chemotherapeutic treatment protocols.

These cellular tests are cumbersome and often require the use of various stimulants (e.g., lipopolysaccharide or anti-CD3 antibody).

Further, clinical efficacy of these compounds could not be correctly predicted, as it could only be measured in terms of patient response, which usually requires a minimum of several months of treatment.

Images